New substituted indolinones, their manufacture and their use as medicaments

ABSTRACT

The present invention relates to substituted indolinones of general formula  
                 
wherein 
     R 1  to R 6  and X are defined as in claim  1 , the isomers and the salts thereof, in particular the physiologically acceptable salts thereof which have valuable pharmacological properties, especially an inhibitory effect on various receptor-tyrosine kinases, and cycline/CDK complexes as well as on the proliferation of endothelial cells and various tumour cells, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

APPLICATION DATA

This application is a continuation of U.S. Ser. No. 10/069,557 filedJul. 22, 2002 which is a 35 USC § 371 case of PCT EP 00/08149 which inturn claims priority to German cases DE 199 40 829.7 filed Aug. 27, 1999and 100 29 285.2 filed Jun. 14, 2000.

The present invention relates to new substituted indolinones of generalformula

the isomers thereof, the salts thereof, particularly the physiologicallyacceptable salts thereof which have valuable properties.

The above compounds of general formula I wherein R₄ denotes a hydrogenatom or a prodrug group have valuable pharmacological properties, inparticular an inhibiting effect on various kinases, especially receptortyrosine kinases such as VEGFR2, PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR,HER2, IGF1R and HGFR, as well as complexes of CDK's (Cycline DependentKinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9with their specific cyclines (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H.I and K) and to viral cycline (cf. L. Mengtao in J. Virology 71 (3),1984-1991 (1997)), to the proliferation of cultivated human cells, inparticular endothelial cells, e.g. in angiogenesis, but also to theproliferation of other cells, in particular tumour cells.

The other compounds of the above general formula I wherein R₄ does notdenote a hydrogen atom or a prodrug group are valuable intermediateproducts for preparing the abovementioned compounds.

The present invention thus relates to the above compounds of generalformula I, whilst those compounds wherein R₄ denotes a hydrogen atom ora prodrug group have valuable pharmacological properties, pharmaceuticalcompositions containing the pharmacologically active compounds, the usethereof and processes for preparing them.

In the above general formula I

-   X denotes an oxygen or sulphur atom,-   R₁ denotes a C₂₋₃-alkenyl, C₂₋₃-alkynyl, aryl, aryl-C₁₋₃-alkyl,    heteroaryl, heteroaryl-C₁₋₃-alkyl, trifluoromethyl or cyano group,-   a hydroxy, C₁₋₃-alkoxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl,    aryloxy or heteroaryloxy group,-   a mercapto, C₁₋₃-alkylsulphenyl, phenylsulphenyl, benzylsulphenyl,    C₁₋₃-alkylsulphinyl, phenylsulphinyl, benzylsulphinyl,    C₁₋₃-alkylsulphonyl, phenylsulphonyl, benzylsulphonyl, sulpho,    C₁₋₃-alkoxysulphonyl, phenoxysulphonyl or benzyloxysulphonyl group,-   an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,    hydroxycarbonyl-C₁₋₃-alkylamino,    N—(C₁₋₃-alkyl)-hydroxycarbonyl-C₁₋₃-alkylamino,    C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino,    N—(C₁₋₃-alkyl)-C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino, phenylamino,    N-phenyl-C₁₋₃-alkylamino, N,N-diphenylamino, benzylamino,    N-benzyl-C₁₋₃-alkylamino, N,N-dibenzylamino,    C₁₋₃-alkylcarbonylamino, benzoylamino or benzylcarbonylamino group    or an N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino group wherein the two    alkyl groups may be replaced by a C₂₋₅-n-alkylene bridge or wherein    one or both alkyl groups may be replaced by a phenyl or benzyl    group,-   a C₁₋₃-alkylsulphonylamino, phenylsulphonylamino or    benzyl-sulphonylamino group or an    N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group wherein the two alkyl    groups may be replaced by a C₂₋₅-n-alkylene bridge or wherein one or    both alkyl groups may be replaced by a phenyl or benzyl group,-   an aminosulphonyl, C₁₋₃-alkylaminosulphonyl, phenylaminosulphonyl,    benzylaminosulphonyl, di-(C₁₋₃-alkyl)-aminosulphonyl,    N,N-diphenyl-aminosulphonyl or N,N-dibenzyl-aminosulphonyl group,-   a phosphono, (C₁₋₃-alkoxy)PO(H), (C₁₋₃-alkoxy)PO(C₁₋₃-alkyl),    (C₁₋₃-alkoxy)PO(OH), di-(C₁₋₃-alkoxy)-PO or    (C₂₋₄-n-alkylenedioxy)-PO group,-   a ureido group optionally mono-, di- or trisubstituted by C₁₋₃-alkyl    groups,-   a 4- to 7-membered cycloalkyleneimino or cycloalkyleneiminosulphonyl    group, wherein in each case the methylene group in the 4 position of    a 6- or 7-membered cycloalkyleneimino group may be replaced by an    oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or    —N(C₁₋₃-alkyl) group,-   R₂ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,-   a C₁₋₆-alkyl or trifluoromethyl group,-   a hydroxy, C₁₋₃-alkoxy, mercapto, C₁₋₃-alkylsulphenyl,    C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl, sulpho,    C₁₋₃-alkoxy-sulphonyl, aminosulphonyl, C₁₋₃-alkylaminosulphonyl or    di-(C₁₋₃-alkyl)-aminosulphonyl group,-   a nitro, amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group,-   a C₁₋₃-alkylcarbonyl, cyano, carboxy, C₁₋₃-alkoxycarbonyl,    aminocarbonyl, C₁₋₃-alkylaminocarbonyl or    di-(C₁₋₃-alkyl)-aminocarbonyl group,-   a phosphono, (C₁₋₃-alkoxy)PO(H), (C₁₋₃-alkoxy)PO(C₁₋₃-alkyl),    (C₁₋₃-alkoxy)PO(OH) or di-(C₁₋₃-alkoxy)-PO group,-   a 4- to 7-membered cycloalkyleneimino, cycloalkyleneiminocarbonyl or    cycloalkyleneiminosulphonyl group, wherein in each case the    methylene group in the 4 position of a 6- or 7-membered    cycloalkyleneimino group may be replaced by an oxygen or sulphur    atom, by a sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group, or-   R₁ and R₂ together denote a methylenedioxy, ethylenedioxy,    n-propylene, n-butylene or 1,4-butadienylene group,-   R₃ denotes a hydrogen atom, denotes a C₁₋₆-alkyl, C₃₋₇-cycloalkyl,    trifluoromethyl or heteroaryl group,-   a phenyl or naphthyl group optionally mono- or disubstituted by a    fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl,    C₁₋₃-alkyl or C₁₋₃-alkoxy group, whilst in the case of    disubstitution the substituents may be identical or different, which    may additionally be substituted    -   by a hydroxy, hydroxy-C₁₋₃-alkyl or C₁₋₃-alkoxy-C₁₋₃-alkyl        group,    -   by a cyano, cyano-C₁₋₃-alkyl, cyano-C₂₋₃-alkenyl,        cyano-C₂₋₃-alkynyl, carboxy, carboxy-C₁₋₃-alkyl,        carboxy-C₂₋₃-alkenyl, carboxy-C₂₋₃-alkynyl, C₁₋₃-alkoxycarbonyl,        C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl, C₁₋₃-alkoxycarbonyl-C₂₋₃-alkenyl        or C₁₋₃-alkoxycarbonyl-C₂₋₃-alkynyl group,    -   by a C₁₋₃-alkylcarbonyl, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkylcarbonyl-C₂₋₃-alkenyl or        C₁₋₃-alkylcarbonyl-C₂₋₃-alkynyl group,    -   by an aminocarbonyl, aminocarbonyl-C₁₋₃-alkyl,        amino-carbonyl-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkynyl,        C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkylaminocarbonyl-C₂₋₃-alkenyl,        C₁₋₃-alkylaminocarbonyl-C₂₋₃-alkynyl,        di-(C₁₋₃-alkyl)-aminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₂₋₃-alkenyl or        di-(C₁₋₃-alkyl)-aminocarbonyl-C₂₋₃-alkynyl group,    -   by a nitro, nitro-C₁₋₃-alkyl, nitro-C₂₋₃-alkenyl or        nitro-C₂₋₃-alkynyl group,    -   by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,        amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl or        di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl group,    -   by a C₁₋₃-alkylcarbonylamino,        C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        C₁₋₃-alkylsulphonylamino, C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl,        N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino or        N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl group,    -   by a 4- to 7-membered cycloalkyleneimino,        cycloalkyleneiminocarbonyl, cycloalkyleneiminosulphonyl,        cycloalkyleneimino-C₁₋₃-alkyl,        cycloalkyleneiminocarbonyl-C₁₋₃-alkyl or        cycloalkyleneiminosulphonyl-C₁₋₃-alkyl group, wherein in each        case the methylene group in the 4 position of a 6- or 7-membered        cycloalkyleneimino group may be replaced by an oxygen or sulphur        atom, by a sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group,    -   or by a heteroaryl or heteroaryl-C₁₋₃-alkyl group,-   R₄ denotes a hydrogen atom, a C₁₋₃-alkyl group or a prodrug group,-   R₅ denotes a hydrogen atom or a C₁₋₃-alkyl group and-   R₆ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,-   a trifluoromethyl or heteroaryl group, a C₁₋₃-alkoxy group    optionally substituted by 1 to 3 fluorine atoms, an    amino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₂₋₃-alkoxy or    benzylamino-C₂₋₃-alkoxy group, a cycloalkyleneimino-C₂₋₃-alkoxy    group with 4 to 7 ring members, a di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkoxy    or C₁₋₃-alkylmercapto group,-   a nitro, cyano, carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,    C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,    piperidinocarbonyl or tetrazolyl group,-   a C₁₋₃-alkylcarbonylamino group optionally substituted at the    nitrogen atom by a C₁₋₃-alkyl group,-   an imidazolyl or piperazino group optionally substituted at the    imino group by a C₁₋₃-alkyl group,-   a C₁₋₄-alkyl group, which may be terminally substituted    -   by a hydroxy, C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl, amino,        C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, phenylamino,        N-phenyl-C₁₋₃-alkylamino, phenyl-n-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino or        di-(phenyl-n-C₁₋₃-alkyl)-amino group,    -   by a 4- to 7-membered cycloalkyleneimino group wherein        -   a methylene group linked to the imino group may be replaced            by a carbonyl or sulphonyl group or        -   one or two hydrogen atoms may each be replaced by a            C₁₋₃-alkyl group and/or        -   in each case the methylene group in the 4 position of a 6-            or 7-membered cycloalkyleneimino group may be substituted by            a carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,            C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,            phenyl-n-C₁₋₃-alkylamino or            N—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino group or        -   may be replaced by an oxygen or sulphur atom, by a            sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group,    -   by a 5- to 7-membered cycloalkenyleneimino group wherein the        double bond is isolated from the nitrogen atom,    -   by a C₄₋₇-cycloalkylamino, N—(C₁₋₃-alkyl)-C₄₋₇-cycloalkylamino        or C₅₋₇-cycloalkenylamino group wherein position 1 of the ring        is not involved in the double bond and wherein the nitrogen atom        may be substituted by a C₁₋₃-alkyl group,    -   by a C₁₋₃-alkylcarbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino, aminocarbonyl,        C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group,-   or R₆ denotes a group of formula    —N(R_(a))—CO—(CH₂)_(n)—Rb  (II),    wherein    -   R_(a) denotes a C₁₋₃-alkyl group,    -   n one of the numbers 0, 1 or 2 and    -   R_(b) denotes an amino, C₁₋₄-alkylamino, phenylamino,        N—(C₁₋₄-alkyl)-phenylamino, benzylamino, N—        (C₁₋₄-alkyl)-benzylamino or di-(C₁₋₄-alkyl)-amino group or a 4-        to 7-membered cycloalkyleneimino group, wherein in each case the        methylene group in the 4 position of a 6- or 7-membered        cycloalkyleneimino group may be replaced by an oxygen or sulphur        atom, by a sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group,        a group of formula        —N(R_(c))—(CH₂)_(m)—(CO)_(o)—Rd  (III),        wherein    -   R_(c) denotes a C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl, arylcarbonyl,        benzylcarbonyl, C₁₋₃-alkylsulphonyl, arylsulphonyl or        benzylsulphonyl group,    -   m denotes one of the numbers 1, 2, 3 or 4,    -   o denotes one of the numbers 0 or 1 and    -   R_(d) has the meanings given for R_(b) hereinbefore or denotes a        di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkylamino group optionally        substituted in the 1 position by a C₁₋₃-alkyl group,-   or an N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group,-   whilst additionally any carboxy, amino or imino group present may be    substituted by a group which can be cleaved in vivo (prodrug group),-   and by a group which can be cleaved in vivo from an imino or amino    group is meant, for example, a hydroxy group, an acyl group such as    the benzoyl or pyridinoyl group or a C₁₋₁₆-alkanoyl group such as    the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl    group, an allyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl group such    as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,    isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl,    pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl,    nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,    dodecyloxycarbonyl or hexadecyloxycarbonyl group, a    phenyl-C₁₋₆-alkoxycarbonyl group such as the benzyloxycarbonyl,-   phenylethoxycarbonyl or phenylpropoxycarbonyl group, a    C₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,    C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl or    R_(e)CO—O—(R_(f)CR_(g))—O—CO group wherein    -   R_(e) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or        phenyl-C₁₋₃-alkyl group,    -   R_(f) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or        phenyl group and    -   R_(g) denotes a hydrogen atom, a C₁₋₃-alkyl or        R_(e)CO—O—(R_(f)CR_(g))—O group wherein R_(e) to R_(g) are as        hereinbefore defined,-   and additionally the phthalimido group may be used for an amino    group, whilst the abovementioned ester groups may also be used as a    group which can be converted in vivo into a carboxy group,-   furthermore the term an aryl group denotes a phenyl or naphthyl    group optionally mono- or disubstituted by a fluorine, chlorine,    bromine or iodine atom or by a trifluoromethyl, C₁₋₃-alkyl or    C₁₋₃-alkoxy group, whilst in the case of disubstitution the    substituents may be identical or different, and-   by a heteroaryl group is meant a monocyclic 5 or 6-membered    heteroaryl group optionally substituted by one or two C₁₋₃-alkyl    groups, whilst the 6-membered heteroaryl group contains one, two or    three nitrogen atoms and the 5-membered heteroaryl group contains an    imino group optionally substituted by a C₁₋₃-alkyl group, an oxygen    or sulphur atom or an imino group optionally substituted by a    C₁₋₃-alkyl group and an oxygen or sulphur atom or one or two    nitrogen atoms, and more-over a phenyl ring may be fused to the    abovementioned mono-cyclic heterocyclic groups via two adjacent    carbon atoms.

Particular mention should be made of the compounds of the abovementionedgeneral formula I, wherein

-   X and R₁ to R₅ are as hereinbefore defined and-   R₆ is as hereinbefore defined, with the exception of an    aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, piperidinocarbonyl or tetrazolyl    group,-   an imidazolyl or piperazino group optionally substituted by a    C₁₋₃-alkyl group at the imino group,-   a C₁₋₄-alkyl group, the terminal carboxy, C₁₋₃-alkoxycarbonyl group,-   an N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group-   or a group of formula    —N(R_(c))—(CH₂)_(m)—(CO)_(o)—R_(d)  (III),    wherein    -   R_(c) denotes a C₁₋₃-alkyl group.

Preferred compounds of the above general formula I are those wherein

-   X denotes an oxygen atom,-   R₁ denotes a C₁₋₃-alkoxy, trifluoromethyl, di-(C₁₋₃-alkyl)-amino,    pyrrolidino or pyrrolo group,-   an amino or C₁₋₃-alkylamino group wherein an amino-hydrogen atom may    be replaced by a C₁₋₃-alkylcarbonyl, phenyl-C₁₋₃-alkylcarbonyl,    benzoyl, aminocarbonyl, C₁₋₃-alkylsulphonyl, phenylsulphonyl,    carboxy-C₁₋₃-alkyl or C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl group, or-   a phenyl group optionally substituted by a C₁₋₃-alkyl group,-   R₂ denotes a hydrogen atom or a C₁₋₃-alkoxy group or-   R₁ and R₂ together denote a methylenedioxy group,-   R₃ denotes a C₁₋₃-alkyl or phenyl group or a phenyl group    substituted by a cyano, amino-C₁₋₃-alkyl or    N—(C₁₋₃-alkanoyl)-amino-C₁₋₃-alkyl group,-   R₄ denotes a hydrogen atom,-   R₅ denotes a hydrogen atom and-   R₆ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,-   a trifluoromethyl, 4-(C₁₋₃-alkyl)-piperazino, pyridinyl, imidazolyl,    tetrazolyl, C₁₋₃-alkoxy or C₁₋₃-alkylmercapto group,-   a nitro, cyano, carboxy or C₁₋₃-alkyloxycarbonyl group or a    C₁₋₃-alkylcarbonylamino group optionally substituted at the nitrogen    atom by a C₁₋₃-alkyl group,-   a piperidinocarbonyl group or an aminocarbonyl group optionally    substituted by one or two C₁₋₃-alkyl groups,-   a C₁₋₃-alkyl group, which may be terminally substituted    -   by an amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,        phenylamino, N-phenyl-C₁₋₃-alkylamino,        phenyl-n-C₁₋₃-alkyl-amino,        N—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino or        di-(phenyl-n-C₁₋₃-alkyl)-amino group, by a pyrrolidino,        piperidino, hexamethyleneimino, morpholino, thiomorpholino,        1-oxido-thiomorpholino or piperazino group,        -   whilst the piperidino group may additionally be substituted            by one or two C₁₋₃-alkyl groups or by a carboxy,            C₁₋₃-alkoxycarbonyl, aminocarbonyl,            C₁₋₃-alkylaminocarbonyl-di-(C₁₋₃-alkyl)-aminocarbonyl or            N—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino group,    -   by a C₅₋₇-cycloalkylamino or C₅₋₇-cycloalkenylamino group        wherein position 1 of the ring is not involved in the double        bond,    -   by a C₁₋₃-alkylcarbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino, carboxy,        C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl or        di-(C₁₋₃-alkyl)-aminocarbonyl group,-   a C₁₋₃-alkoxy group, which is terminally substituted by an amino,    C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group,-   a group of formula    —N(R_(a))—CO—(CH₂)_(n)—R_(b)  (II),    wherein    -   R_(a) denotes a C₁₋₃-alkyl group,    -   n denotes one of the numbers 0, 1 or 2 and    -   R_(b) denotes an amino, C₁₋₄-alkylamino or di-(C₁₋₄-alkyl)-amino        group or a pyrrolidino, piperidino, hexamethyleneimino,        morpholino, thiomorpholino, 1-oxido-thiomorpholino or piperazino        group,        a group of formula        —N(R_(c))—(CH₂)_(m)—(CO)_(o)—R_(d)  (III),        wherein    -   R_(c) denotes a C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl or        C₁₋₃-alkylsulphonyl group,    -   m denotes one of the numbers 1, 2, 3 or 4,    -   o denotes one of the numbers 0 or 1 and    -   R_(d) has the meanings given for Rb hereinbefore or denotes a        di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkylamino group optionally        substituted in the 1 position by a C₁₋₃-alkyl group,        or an N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group,        the isomers and the salts thereof.

Particularly preferred compounds of the above general formula I arethose wherein

-   X denotes an oxygen atom,-   R₁ denotes a methoxy, ethoxy, trifluoromethyl, phenyl, methylphenyl,    dimethylamino, pyrrolidino or pyrrolo group,-   an amino group which may be substituted by a methyl, carboxymethyl,    methoxycarbonylmethyl, acetyl, phenylacetyl, benzoyl,    methanesulphonyl, benzolsulphonyl or aminocarbonyl group,-   R₂ denotes a hydrogen atom, a methoxy or ethoxy group or-   R₁ and R₂ together denote a methylenedioxy group,-   R₃ denotes an ethyl group or a phenyl group optionally substituted    by a cyano, aminomethyl or N-acetyl-aminomethyl group,-   R₄ denotes a hydrogen atom,-   R₅ denotes a hydrogen atom and-   R₆ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,-   a methyl, trifluoromethyl, methoxy, ethoxy, methylmercapto, cyano,    carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,    dimethylaminocarbonyl, piperidinocarbonyl, nitro,    4-methyl-piperazino, imidazolyl, pyridinyl or tetrazolyl group,-   an ethyloxy or n-propyloxy group terminally substituted by a    dimethylamino group,-   a methyl or ethyl group substituted by a carboxy, methoxycarbonyl,    ethoxycarbonyl, aminocarbonyl or dimethylaminocarbonyl group,-   a C₁₋₃-alkyl group, which may be terminally substituted    -   by an amino, C₁₋₄-alkylamino, cyclohexylamino, benzylamino or        phenylamino group wherein a hydrogen atom of the amino-nitrogen        atom may be replaced in each case by a C₁₋₃-alkyl, benzyl,        acetyl or dimethylaminocarbonyl group,    -   by a piperidino group optionally substituted by one or two        methyl groups,    -   by a piperidino group substituted by a carboxy, methoxycarbonyl,        ethoxycarbonyl or dimethylaminocarbonyl group,    -   by a pyrrolidino, 3,4-dehydro-piperidino, hexa-methyleneimino,        morpholino, thiomorpholino, 1-oxo-thio-morpholino or piperazino        group,        a C₁₋₃-alkylamino group wherein the hydrogen atom of the        amino-nitrogen atom is replaced    -   by an ethyl or n-propyl group, each of which is terminally        substituted by a dimethylamino group,    -   by a C₂₋₃-alkanoyl group which may be substituted in the 2 or 3        position by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,        pyrrolidino, piperidino, morpholino or piperazino group,    -   by an aminocarbonyl, methylaminocarbonyl,        dimethyl-aminocarbonyl, piperidinocarbonyl or methanesulphonyl        group,    -   and additionally the C₁₋₃-alkyl moiety of the C₁₋₃-alkylamino        group may be substituted        -   by an aminocarbonyl group,        -   by a C₁₋₃-alkylaminocarbonyl or            di-(C₁₋₃-alkyl)-aminocarbonyl group wherein a C₂₋₃-alkyl            moiety may additionally be terminally substituted by a            dimethylamino group,        -   by a pyrrolidinocarbonyl, piperidinocarbonyl,            morpholinocarbonyl or piperazinocarbonyl group,        -   whilst the C₂₋₃-alkyl moiety of the above-mentioned            C₁₋₃-alkylamino group may also be terminally substituted by            an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,            pyrrolidino, piperidino, morpholino or piperazino group,            in particular those compounds of the above general formula I            wherein-   either X, R₁ and R₃ to R₆ are as hereinbefore defined and R₂ denotes    a hydrogen atom,-   or X and R₃ to R₆ are as hereinbefore defined, R₁ and R₂, which may    be identical or different, each denotes a C₁₋₃-alkoxy group,-   the isomers and the salts thereof.

Quite specially preferred compounds of the above general formula I arethose wherein

-   X denotes an oxygen atom,-   R₁ denotes an amino, methoxy or ethoxy group,-   R₂ denotes a hydrogen atom or in position 5 a methoxy or ethoxy    group,-   R₃ denotes a methyl, ethyl or phenyl group,-   R₄ and R₅ each denote a hydrogen atom and-   R₆ denotes a methyl or ethyl group substituted by a methylamino,    ethylamino, piperidino or 4-(dimethylaminocarbonyl)-piperidino    group, wherein the amino-hydrogen atom of the methylamino- and    ethylamino group is replaced by a methyl or benzyl group, an    N-dimethylaminomethylcarbonyl-N-methyl-amino group or an    N-acetyl-N—(C₂₋₃-alkyl)-amino group wherein the C₂₋₃-alkyl moiety in    each case is terminally substituted by a dimethylamino group,-   and the salts thereof.

The following particularly useful compounds of general formula I arementioned by way of example:

-   (a)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone,-   (b)    3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone,-   (c)    3-(Z)-{1-(4-(dimethylamino-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone,-   (d)    3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone,-   (e)    3-(Z)-(1-{4-[2-(4-dimethylcarboxamide-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone,-   (f)    3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    and-   (g)    6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone,-   (h)    3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylamino-ethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and-   (i)    3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylamino-propyl)-amino]1-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   as well as the salts thereof.

According to the invention, the new compounds may be obtained, forexample, by the following methods known in principle from theliterature:

-   a. reaction of a compound of general formula    wherein-   X and R₁ to R₃ are defined as in claims 1 to 4,-   R₇ denotes a hydrogen atom, a protecting group for the nitrogen atom    of the lactam group or a bond to a solid phase and-   Z₁ denotes a halogen atom, a hydroxy, alkoxy or arylalkoxy-group,    e.g. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy    group,-   with an amine of general formula    wherein    R₅ and R₆ are defined as in claims 1 to 4, and if necessary    subsequently cleaving any protecting group used for the nitrogen    atom of the lactam group or cleaving from a solid phase.

A protecting group for the nitrogen atom of the lactam group might befor example an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl orbenzyloxycarbonyl group and

-   the solid phase might be a Rink resin such as a    p-benzyloxybenzylalcohol resin, whilst the bond may conveniently be    formed via an intermediate member such as a    2,5-dimethoxy-4-hydroxy-benzyl derivative.

The reaction is conveniently carried out in a solvent such asdimethylformamide, toluene, acetonitrile, tetrahydrofuran,dimethylsulphoxide, methylene chloride or mixtures thereof, optionallyin the presence of an inert base such as triethylamine,N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperaturesbetween 20 and 175° C., whilst any protecting group used can be cleavedsimultaneously by transamidation.

If Z₁ in a compound of general formula IV denotes a halogen atom, thereaction is preferably carried out in the presence of an inert base attemperatures between 20 and 120° C.

If Z₁ in a compound of general formula IV denotes a hydroxy, alkoxy oraralkoxy group, the reaction is preferably carried out at temperaturesbetween 20 and 200° C.

If any protecting group used subsequently has to be cleaved, this isconveniently carried out either hydrolytically in an aqueous oralcoholic solvent, e.g. in methanol/water, ethanol/water,isopropanol/water, tetrahydrofuran/water, dioxane/water,dimethylformamide/water, methanol or ethanol in the presence of analkali metal base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.,

-   or advantageously by transamidation with a primary or secondary    organic base such as butylamine, dimethylamine or piperidine in a    solvent such as methanol, ethanol, dimethylformamide and mixtures    thereof or in an excess of the amine used at temperatures between 0    and 100° C., preferably at temperatures between 10 and 50° C.

Any solid phase used is preferably cleaved using trifluoroacetic acidand water in the presence of a dialkylsulphide such as dimethylsulphideat temperatures between 0 and 35° C., preferably at ambient temperature.

-   b. In order to prepare a compound of general formula I wherein R₁    denotes an amino group:-   Reduction of a compound of general formula

The reduction of a nitro group is preferably carried out byhydrogenolysis, e.g. with hydrogen in the presence of a catalyst such aspalladium/charcoal or Raney nickel in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid or glacial acetic acid at temperatures between 0 and50° C., but preferably at ambient temperature, and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar.

-   c. In order to prepare a compound of general formula I wherein R₁    or/and R₂ denotes one of the abovementioned substituted sulphinyl or    sulphonyl groups:-   oxidation of a compound of general formula    wherein    R₃ to R₆ are defined as in claims 1 to 4 and one of the groups R₁    and R₂′ denotes one of the substituted mercapto or sulphinyl groups    mentioned above for R₁ and R₂ and the other one assumes the meanings    given above for R₁ or R₂ with the exception of the mercapto or    sulphinyl groups or both groups R₁′ and R₂′, denote one of the    substituted mercapto or sulphinyl groups mentioned above for R₁ and    R₂.

The oxidation is preferably carried out in a solvent or mixture ofsolvents, e.g. in water, water/pyridine, acetone, methylene chloride,acetic acid, acetic acid/acetic anhydride, dilute sulphuric acid ortrifluoroacetic acid, expediently at temperatures between −80 and 100°C., depending on the oxidising agent used.

In order to prepare a corresponding sulphinyl compound of generalformula I the oxidation is expediently carried out with one equivalentof the oxidising agent used, e.g. with hydrogen peroxide in glacialacetic acid, trifluoroacetic acid or formic acid at 0 to 20° C. or inacetone at 0 to 60° C., with a peracid such as performic acid in glacialacetic acid or trifluoroacetic acid at 0 to 50° C. or withm-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at−20 to 80° C., with sodium metaperiodate in aqueous methanol or ethanolat −15 to 25° C., with bromine in glacial acetic acid or aqueous aceticacid optionally in the presence of a weak base such as sodium acetate,with N-bromosuccinimide in ethanol, with tert.butylhypochlorite inmethanol at −80 to −30° C., with iodobenzodichloride in aqueous pyridineat 0 to 50° C., with nitric acid in glacial acetic acid at 0 to 20° C.,with chromic acid in glacial acetic acid or in acetone at 0 to 20° C.and with sulphurylchloride in methylene chloride at −70° C., theresulting thioether-chlorine complex is expediently hydrolysed withaqueous ethanol.

In order to prepare a sulphonyl compound of general formula I theoxidation is expediently carried out starting from a correspondingsulphinyl compound with one or more equivalents of the oxidising agentused or starting from a corresponding mercapto compound, expedientlywith two or more equivalents of the oxidising agent used, e.g. withhydrogen peroxide in glacial acetic acid/acetic anhydride,trifluoroacetic acid or in formic acid at 20 to 100° C. or in acetone at0 to 60° C., with a peracid such as performic acid or m-chloroperbenzoicacid in glacial acetic acid, trifluoroacetic acid, methylene chloride orchloroform at temperatures between 0 and 60° C., with nitric acid inglacial acetic acid at 0 to 20° C., with chromic acid, sodium periodateor potassium permanganate in acetic acid, water/sulphuric acid or inacetone at 0 to 20° C.

If according to the invention a compound of general formula I isobtained which contains an alkoxycarbonyl group, this can be convertedby hydrolysis into a corresponding carboxy compound, or

-   If a compound of general formula I is obtained which contains an    amino or alkylamino group, this may be converted by alkylation or    reductive alkylation into a corresponding alkylamino, dialkylamino    or pyrrolidino compound, or-   If a compound of general formula I is obtained which contains an    amino or alkylamino group, this may be converted by acylation into a    corresponding acyl compound, or-   If a compound of general formula I is obtained which contains an    amino or alkylamino group, this may be converted by sulphonation    into a corresponding sulphonyl compound, for example into the    corresponding alkylsulphonylamino, phenylsulphonylamino,    benzylsulphonylamino or N-alkyl-alkyl-sulphonylamino group, or-   If a compound of general formula I is obtained which contains an    amino group, this can be converted by a reaction of condensation    into a corresponding pyrrolo compound, or-   If a compound of general formula I is obtained which contains a    carboxy group, this may be converted by esterification or amidation    into a corresponding ester or aminocarbonyl compound, or-   If a compound of general formula I is obtained which contains a    cyano group, this can be converted by reduction into a corresponding    aminomethyl compound, or

If a compound of general formula I is obtained which contains an aminoor alkylamino group, this may be converted by reaction with cyanic acidor a corresponding isocyanate into a corresponding ureido compound.

The subsequent hydrolysis is preferably carried out in an aqueoussolvent, e.g. in water, methanol/water, ethanol/water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such aslithium hydroxide, sodium hydroxide or potassium hydroxide attemperatures between 0 and 100° C., preferably at temperatures between10 and 50° C.

The subsequent reductive alkylation is preferably carried out in asuitable solvent such as methanol, methanol/water,methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane,methylene chloride or dimethylformamide optionally with the addition ofan acid such as hydrochloric acid in the presence of catalyticallyactivated hydrogen, e.g. hydrogen in the presence of Raney nickel,platinum or palladium/charcoal, or in the presence of a metal hydridesuch as sodium borohydride, sodium cyanoborohydride, lithium borohydrideor lithium aluminium hydride at temperatures between 0 and 100° C.,preferably at temperatures between 20 and 80° C.

The subsequent alkylation is carried out with an alkylating agent suchas an alkyl halide or dialkyl sulphate such as methyliodide,dimethylsulphate or propylbromide preferably in a solvent such asmethanol, ethanol, methylene chloride, tetrahydrofuran, toluene,dioxane, dimethylsulphoxide or dimethylformamide optionally in thepresence of an inorganic or a tertiary organic base such as potassiumcarbonate, triethylamine, N-ethyl-diisopropylamine, pyridine ordimethylaminopyridine, preferably at temperatures between 20° C. and theboiling temperature of the solvent used.

The subsequent acylation is preferably carried out in a solvent such asmethylene chloride, diethylether, tetrahydrofuran, toluene, dioxane,acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in thepresence of an inorganic or a tertiary organic base, preferably attemperatures between 20° C. and the boiling temperature of the solventused. The acylation with a corresponding acid is preferably carried outin the presence of a dehydrating agent, e.g. in the presence of isobutylchloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate,2,2-dimethoxypropane, tetramethoxysilane, thionylchloride,trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole,N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, andoptionally with the addition of a base such as pyridine,4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine,conveniently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C., and the acylation with acorresponding reactive compound such as an anhydride, ester, imidazolideor halide thereof is optionally carried out in the presence of atertiary organic base such as triethylamine, N-ethyl-diisopropylamine,N-methyl-morpholine or pyridine at temperatures between 0 and 150° C.,preferably at temperatures between 50 and 100° C.

The subsequent sulphonation is preferably carried out in a solvent suchas methylene chloride, diethylether, tetrahydro-furan, toluene, dioxane,acetonitrile, dimethylsulphoxide or dimethylformamide optionally in thepresence of an inorganic or tertiary organic base, preferably attemperatures between 20° C. and the boiling temperature of the solventused. The sulphonation is carried out with a corresponding reactivecompound, for example the sulphonylhalides, optionally in the presenceof a tertiary organic base such as triethylamine,N-ethyl-diisopropylamine, N-methyl-morpholine, pyridine ordimethylaminopyridine at temperatures between 0 and 150° C., preferablyat temperatures between 50 and 100° C.

The subsequent condensation for converting an amino group into a pyrrologroup is expediently carried out in a solvent such as dimethylformamide,toluene, acetonitrile, tetrahydrofuran, dimethylsulphoxide, methylenechloride or mixtures thereof, preferably in the presence of a acid suchas formic acid, glacial acetic acid or trifluoroacetic acid or using theacid as the sole solvent with condesable 1,4-difunctional n-butylene ortetrahydrofuran derivatives, for example with2,5-dimethoxytetrahydrofuran or 2,5-hexanedione, at temperatures between0 and 120° C. or the boiling temperature of the reaction mixture.

The subsequent esterification or amidation is expediently carried out byreacting a corresponding reactive carboxylic acid derivative with acorresponding alcohol or amine as described hereinbefore.

The subsequent reduction of a cyano group is preferably carried out in asuitable solvent such as methanol, methanol/water,methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane,methylene chloride or dimethylformamide optionally with the addition ofmethanolic ammonia with hydrogen in the presence of a hydrogenationcatalyst, e.g. in the presence of Raney nickel or palladium/charcoal, ata hydrogen pressure of 1 to 5 bar, preferably at temperatures between20° C. and the boiling temperature of the solvent used.

The subsequent reaction with a cyanic acid or a corresponding isocyanateis preferably carried out in a suitable solvent such as ethanol,tetrahydrofuran or dioxane at temperatures between 0° C. and the boilingtemperature of the reaction mixture; the cyanic acid used is expedientlyprepared in the reaction mixture by reacting a salt of cyanic acid withan acid, for example by reacting potassium cyanate with glacial aceticacid.

In the reactions described hereinbefore, any reactive groups presentsuch as carboxy, amino, alkylamino or imino groups may be protectedduring the reaction by conventional protecting groups which are cleavedagain after the reaction.

For example, a protecting group for a carboxyl group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup and

-   protecting groups for an amino, alkylamino or imino group may be an    acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,    tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or    2,4-dimethoxybenzyl group and additionally, for the amino group, a    phthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of a acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid or glacial acetic acid at temperatures between 0 and50° C., but preferably at ambient temperature, and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium (IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxane, ethylacetate or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

Moreover, chiral compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained whichoccur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid,aspartic acid, N-acetylaspartic acid or quinic acid. An optically activealcohol may be for example (+)- or (−)-menthol and an optically activeacyl group in amides, for example, may be a (+)- or(−)-menthyloxycarbonyl group.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid, maleic acid ormethanesulphonic acid.

Moreover, if the new compounds of formula I thus obtained contain acarboxy group, they may subsequently, if desired, be converted into thesalts thereof with inorganic or organic bases, particularly forpharmaceutical use into the physiologically acceptable salts thereof.Suitable bases for this purpose include for example sodium hydroxide,potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

The compounds of general formulae IV to VII used as starting materialsare known from the literature in some cases or may be obtained bymethods known from the literature or are described in the Examples.

As already mentioned, the new compounds of general formula I wherein R₄denotes a hydrogen atom or a prodrug group have valuable pharmacologicalproperties, particularly inhibitory effects on various kinases,especially on receptor-tyrosine kinases such as VEGFR2, PDGFRα, PDGFRβ,FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as on complexes ofCDK's (Cycline Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5,CDK6, CDK7, CDK8 and CDK9 with their specific cyclines (A, B1, B2, C,D1, D2, D3, E, F, G1, G2, H, I and K) and on viral cycline, on theproliferation of cultivated human cells, particularly endothelial cells,e.g. in angiogenesis, but also on the proliferation of other cells,particularly tumour cells.

The biological properties of the new compounds were tested by thefollowing standard procedure, as follows:

Human umbilical endothelial cells (HUVEC) were cultivated in IMDM (GibcoBRL), supplemented with 10% foetal calf serum (FBS) (Sigma), 50 μM of9-mercaptoethanol (Fluka), standard antibiotics, 15 μg/ml of endothelialcell growth factor (ECGS, Collaborative Biomedical Products) and 100μg/ml of heparin (Sigma) on gelatine-coated culture dishes (0.2%gelatine, Sigma) at 37° C., under 5% CO₂ in a water-saturatedatmosphere.

In order to investigate the inhibitory activity of the compoundsaccording to the invention the cells were “starved” for 16 hours, i.e.kept in culture medium without growth factors (ECGS+heparin). The cellswere detached from the culture dishes using trypsin/EDTA and washed oncein serum-containing medium. Then they were seeded out in amounts of2.5×10³ cells per well.

The proliferation of the cells was stimulated with 5 ng/ml of VEGF₁₆₅(vascular endothelial growth factor; H. Weich, G B F Braunschweig) and10 μg/ml of heparin. As a control, 6 wells in each dish were notstimulated.

The compounds according to the invention were dissolved in 100%dimethylsulphoxide and added to the cultures in various dilutions astriple measurements, the maximum dimethyl sulphoxide concentration being0.3%.

The cells were incubated for 76 hours at 37° C., then for a further 16hours ³H-thymidine (0.1 μCi/well, Amersham) was added in order todetermine the DNA synthesis. Then the radioactively labelled cells wereimmobilised on filter mats and the radioactivity incorporated wasmeasured in a β-counter. In order to determine the inhibitory activityof the compounds according to the invention the mean value of thenon-stimulated cells was subtracted from the mean value of thefactor-stimulated cells (in the presence or absence of the compoundsaccording to the invention).

The relative cell proliferation was calculated as a percentage of thecontrol (HUVEC without inhibitor) and the concentration of activesubstance which inhibits the proliferation of the cells by 50% (IC₅₀)was determined.

The following Table contains the results found: compound (Example No.)IC₅₀ [μM] 1 0.03 1 (3) 0.27 1 (6) 0.02 1 (8) 0.05 1 (17) 0.04 1 (18)0.04 1 (50) 0.83 3 0.05 4 0.04

In addition the compound of Example 1(6) was tested on mice for itstolerance. The approximate oral LD₅₀ for this compound is over 1,000mg/kg. The compounds of general formula I are therefore well tolerated.

In view of their inhibitory effect on the proliferation of cells,particularly endothelial cells and tumour cells, the compounds ofgeneral formula I are suitable for treating diseases in which theproliferation of cells, particularly endothelial cells, plays a part.

Thus, for example, the proliferation of endothelial cells and theconcomitant neovascularisation constitute a crucial stage in tumourprogression (Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D.and Folkman J., Cell 86, 353-365, (1996)). Furthermore, theproliferation of endothelial cells is also important in haemangiomas, inmetastasisation, rheumatoid arthritis, psoriasis and ocularneovascularisation (Folkman J., Nature Med. 1, 27-31, (1995)). Thetherapeutic usefulness of inhibitors of endothelial cell proliferationwas demonstrated in the animal model for example by O'Reilly et al. andParangi et al. (O'Reilly M. S. et al., Cell 88, 277-285, (1997); ParangiS. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)).

The compounds of general formula I, their tautomers, their stereoisomersor the physiologically acceptable salts thereof are thus suitable, forexample, for treating solid tumours, diabetic retinopathy, rheumatoidarthritis and psoriasis, or other diseases in which cell proliferationor angiogenesis play a part.

By reason of their biological properties the compounds according to theinvention may be used on their own or in conjunction with otherpharmacologically active compounds, for example in tumour therapy, inmonotherapy or in conjunction with other anti-tumour therapeutic agents,for example in combination with Topoisomerase inhibitors (e.g.Etoposide), mitosis inhibitors (e.g. Vinblastin, Taxol), compounds whichinteract with nucleic acids (e.g. cisplatin, Cyclophosphamide,Adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors ofmetabolic processes (e.g. 5-FU etc.), cytokines (e.g. inter-ferons),kinase inhibitos, antibodies, or in conjunction with radiotherapy, etc.These combinations may be administered either simultaneously orsequentially.

For pharmaceutical use the compounds according to the invention aregenerally used for warm-blooded vertebrates, particularly humans, indoses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. Foradministration they are formulated with one or more conventional inertcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethyleneglycol, propyleneglycol,stearylalcohol, carboxymethylcellulose or fatty substances such as hardfat or suitable mixtures thereof in conventional galenic preparationssuch as plain or coated tablets, capsules, powders, suspensions,solutions, sprays or suppositories.

The following Examples are intended to illustrate the present inventionwithout restricting it:

Abbreviations:

-   TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)-uronium    hexafluorophosphate-   HOBt=1-hydroxy-1H-benzotriazole

Preparation of the starting compounds:

EXAMPLE I

1-hydroxy-6-nitro-2-indolinone

2.0 g of 2,4-dinitrophenylacetic acid (prepared according to J. Chem.Soc. 1948, 1717) are dissolved in 40 ml ethanol and 6.0 ml of conc.hydrochloric acid and 4.1 g of tin-(II)-chloride-dihydrate are added inbatches at ambient temperature. The mixture is stirred for 12 hours atambient temperature and for 4 hours at 60° C. After cooling another 2.0g of tin-(II)-chloride-dihydrate are added and the mixture is stirredfor another 12 hours at ambient temperature. The reaction mixture isdiluted with water, extracted with methylene chloride and the organicphase is dried over sodium sulphate. After elimination of the solventthe residue is triturated with ether and the precipitate is filteredoff.

Yield: 0.6 g (35% of theory),

R_(f) value: 0.7 (silica gel, methylene chloride/methanol=9:1)

C₈H₆N₂O₄

ESI mass spectrum: m/z=193 [M−H⁻]

EXAMPLE II

3,4-Diethoxy-phenylacetic acid

0.8 g of 3,4-dihydroxy-phenylacetic acid and 6.9 g of barium hydroxideoctahydrate are dissolved in 50 ml of water and at ambient temperature2.9 ml of diethylsulphate are added dropwise. The solution is stirredfor 2 hours at ambient temperature and for 2 hours at 40° C. After thistime the solution is acidified with saturated potassium hydrogensulphate solution, mixed with ethyl acetate and the suspension isfiltered through Celite. The phases are separated and the ethyl acetatephase is dried over sodium sulphate and concentrated by evaporation. Theresidue obtained is purified through a silica gel column withtoluene/ethyl acetate/ethanol (4:2:1) as eluant.

Yield: 0.5 g (42% of theory),

R_(f) value: 0.5 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₁₂H₁₆O₄

ESI mass spectrum: m/z=223 [M−H⁻]

EXAMPLE III

4,5-diethoxy-2-nitro-phenylacetic acid

0.5 g of 3,4-diethoxy-phenylacetic acid are placed in 10 ml of aceticacid p.a. and 0.5 ml of 65% nitric acid are added dropwise, so that theinternal temperature does not rise above 15° C. The mixture is thenheated to 40° C. for 0.5 hours. After this time the solution is pouredonto ice water and the precipitate formed is suction filtered. Theproduct is washed with water and dried at 100° C.

Yield: 0.3 g (57% of theory),

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₁₂H₁₅NO₆

ESI mass spectrum: m/z=292 [M+Na⁺]

EXAMPLE IV

tert.butyl 2-nitro-4-trifluormethyl-phenylacetate

2.6 g of potassium-tert.butoxide are placed in 45 ml ofdimethylformamide and at an internal temperature of −5° C. 1.3 ml of3-nitro-trifluorotoluene and 1.5 ml of tert.butyl chloroacetate in 1 mlof dimethylformamide are added dropwise. The mixture is stirred foranother 5 minutes and the solution is then poured onto ice water and theprecipitate formed is suction filtered.

Yield: 2.5 g (82% of theory),

R_(f) value: 0.4 (silica gel, petroleum ether/ethyl acetate=10:1)

Melting point: 45° C.

EXAMPLE V

2-nitro-4-trifluoromethyl-phenylacetic acid

16.7 g of tert.butyl 2-nitro-4-trifluoromethyl-phenylacetate and 50 mlof trifluoroacetic acid are dissolved in 50 ml of methylene chloride andstirred for 3 hours at ambient temperature. After elimination of thesolvent the residue is taken up in petroleum ether/ether (10:1), suctionfiltered and dried in vacuo at 80° C.

Yield: 13.4 g (98% of theory),

R_(f) value: 0.5 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₉H₆F₃NO₄

ESI mass spectrum: m/z=248 [M−H⁻]

EXAMPLE VI

5,6-diethoxy-2-indolinone

1.4 g of 4,5-diethoxy-2-nitro-phenylacetic acid are dissolved in 50 mlof acetic acid, 0.3 g of 10% palladium on carbon is added and themixture is hydrogenated for 1 hour at ambient temperature and 50 psi.The catalyst is filtered off and the filtrate is concentrated byevaporation.

Yield: 1.15 g (100% of theory),

R_(f) value: 0.5 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

The following compounds are prepared analogously to Example VI:

-   (1) 6-trifluoromethyl-2-indolinone    Prepared from 2-nitro-4-trifluoromethyl-phenylacetic acid-   (2) 6-bromo-2-indolinone    Prepared from 4-bromo-6-nitro-phenylacetic acid (according to Chem.    Pharm. bull. (1985), 33, 1414-1418)

EXAMPLE VII

6-phenyl-2-indolinone

2.4 g of 6-bromo-2-indolinone are placed in 60 ml of dimethoxyethane,1.9 g of phenylboric acid in 8 ml of ethanol and 0.3 g oftetrakistriphenylphosphine palladium are added and to this mixture 12 mlof 2N sodium carbonate solution are added dropwise at ambienttemperature. The mixture is stirred for 6 hours at 85° C. After coolingthe catalyst is filtered off, the solvent is eliminated and the residueis washed with 100 ml of water and 20 ml of 1N sodium hydroxidesolution. The residue is purified through a silica gel column withpetroleum ether/ethyl acetate (8:2) as eluant.

Yield: 1.5 g (65% of theory),

R_(f) value: 0.45 (silica gel, petroleum ether/ethyl acetate=1:1)

Melting point: 167-170° C.

The following compound is prepared analogously to Example VII:

-   (1) 6-(2-Tolyl)-2-indolinone    Prepared from 6-bromo-2-indolinone and 2-tolylboric acid

EXAMPLE VIII

1-acetyl-5,6-dimethoxy-2-indolinone

16.0 g of 5,6-dimethoxy-2-indolinone (according to Hahn; Tulus; Chem.Ber. 74, 500 (1941)) are dissolved in 170 ml of acetic anhydride andstirred for more than 3 hours at 130° C. After cooling the residue isfiltered off, washed with ether and dried in vacuo at 100° C.

Yield: 15.8 g (81% of theory),

R_(f) value: 0.8 (silica gel, methylene chloride/methanol=10:1)

C₁₂H₁₃NO₄

ESI mass spectrum: m/z=234 [M−H⁻]

The following compounds are prepared analogously to Example VIII:

-   (1) 1-acetyl-6-methoxy-2-indolinone    Prepared from 6-methoxy-2-indolinone (prepared according to    Quallich, G. J.; Morrissey, P. M.; Synthesis 1993, 51) and acetic    anhydride-   (2) 1-acetyl-5,6-diethoxy-2-indolinone    Prepared from 5,6-diethoxy-2-indolinone and acetic anhydride-   (3) 1-acetyl-6-trifluoromethyl-2-indolinone    Prepared from 6-trifluoromethyl-2-indolinone and acetic anhydride

EXAMPLE IX

1-acetyl-3-(1-ethoxy-1-phenylmethylidene)-5,6-dimethoxy-2-indolinone

10.0 g of 1-acetyl-5,6-dimethoxy-2-indolinone, 29.2 ml of triethylorthobenzoate and 100 ml of acetic anhydride are stirred for 48 hours at120° C. The solvent is eliminated and the residue evaporated withtoluene, combined with ether and the precipitate formed (startingcompound) is suction filtered. The filtrate is concentrated byevaporation and separated through a silica gel column with toluene, thenwith toluene/ethyl acetate (10:1). The product is triturated with ether,suction filtered and dried in vacuo at 100° C.

Yield: 1.4 g (9% of theory),

R_(f) value: 0.5 (silica gel, toluene/ethyl acetate=5:1)

C₂₁H₂₁NO₅

ESI mass spectrum: m/z=390 [M+Na⁺]

The following compounds are prepared analogously to Example IX:

-   (1)    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone    Prepared from 1-acetyl-6-methoxy-2-indolinone, triethyl    orthobenzoate and acetic anhydride-   (2)    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from 1-acetyl-5,6-dimethoxy-2-indolinone, triethyl    orthopropionate and acetic anhydride-   (3)    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone    Prepared from 1-acetyl-5,6-diethoxy-2-indolinone, triethyl    orthopropionate and acetic anhydride-   (4) 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone    Prepared from 6-phenyl-2-indolinone, triethyl orthopropionate and    acetic anhydride-   (5)    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone    Prepared from 6-(2-tolyl)-2-indolinone, triethyl orthopropionate and    acetic anhydride

EXAMPLE X

1-acetyl-3-[1-hydroxy-1-(3-cyanophenyl)-methylidene]-5,6-di-methoxy-2-indolinone

2.0 g of 1-acetyl-5,6-dimethoxy-2-indolinone, 1.3 g of 2-cyanobenzoicacid, 3.3 g of TBTU, 1.6 g of HOBt and 7.5 ml ofN-ethyl-diisopropylamine are dissolved in 30 ml of dimethylformamide andstirred for two days at ambient temperature. After this time thesolution is combined with 400 ml of water and 20 ml of saturatedpotassium hydrogen sulphate solution. The precipitate formed is suctionfiltered, washed with water, a little methanol and a little ether anddried in vacuo at 100° C.

Yield: 2.6 g (84% of theory),

R_(f) value: 0.8 (silica gel, methylene chloride/methanol=5:1)

C₂₀H₁₆N₂O₅

ESI mass spectrum: m/z=363 [M−H⁻]

The following compound is prepared analogously to Example X:

-   (1)    1-acetyl-3-(1-hydroxy-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone    Prepared from 1-acetyl-6-trifluoromethyl-2-indolinone and benzoic    acid

EXAMPLE XI

1-acetyl-3-[1-chloro-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-indolinone

2.5 g of1-acetyl-3-[1-chloro-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-indolinoneand 1.6 g of phosphorus pentachloride are dissolved in 30 ml of tolueneand stirred for 1 hour at 80° C. The suspension is cooled, combined with50 ml of ether and the precipitate formed is suction filtered. Afterwashing with ether the residue is dried in vacuo at 50° C.

Yield: 1.5 g (56% of theory),

R_(f) value: 0.6 (silica gel, methylene chloride/methanol=40:1)

C₂₀H₁₅CN₁₂O₄

ESI mass spectrum: m/z=405/407 [M+Na⁺]

The following compound is prepared analogously to Example XI:

-   (1)    1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone    Prepared from    1-acetyl-3-(1-hydroxy-1-phenyl-methylidene)-6-trifluoromethyl-2-indoline    and phosphorus pentachloride

EXAMPLE XII

3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone

Under a nitrogen atmosphere 4.5 g of diethyl-1-methoxybenzylphosphonate(according to Burkhouse, D.; Zimmer, H.; Synthesis 1984, 330) aredissolved in 40 ml of absolute dimethylformamide and at −40° C. 4.0 g ofpotassium-tert-butoxide are added batchwise and stirred for 15 minutesat −10° C. 3.0 g of 5,6-methylenedioxyisatin (according to Lackey, K.;Sternbach, D. D.; Synthesis 1993, 993) are added to the clear solutionand stirred for 1 hour at ambient temperature. After this time themixture is poured into 20 ml of ice-cold saturated potassium hydrogensulphate solution and extracted with ethyl acetate. The ethyl acetatephase is washed with water, dried over sodium sulphate and concentratedby evaporation. Finally the residue is separated through a silica gelcolumn with toluene/ethyl acetate (5:1). The product obtained can berecrystallised from ether.

Yield: 1.6 g (35% of theory),

R_(f) value: 0.3 (silica gel, toluene/ethyl acetate=5:1)

C₁₇H₁₃NO₄

ESI mass spectrum: m/z=318 [M+Na⁺]

EXAMPLE XIII

1-acetoxy-3-(1-ethoxy-1-phenylmethylidene)-6-nitro-2-indolinone

300 mg of 1-hydroxy-6-nitro-2-indolinone are dissolved in 4.0 ml ofacetic anhydride and 4.0 ml of triethyl orthobenzoate, stirred for 6hours at 110° C., concentrated by evaporation and purified through asilica gel column with methylene chloride as eluant.

Yield: 0.28 g (49% of theory),

R_(f) value: 0.23 (silica gel, methylene chloride)

C₁₉H₁₆N₂O₆

Mass spectrum: m/z=368 [M⁺]

EXAMPLE XIV

3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-nitro-2-indolinone

1.25 g of1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2-indolinone and0.65 g of 4-(piperidin-1-yl-methyl)-aniline are dissolved in 10 ml ofdimethylformamide and stirred for 30 minutes at ambient temperature.After this time 46 mg of palladium on carbon (10%) are added andcarefully hydrogenated for 1 hour at ambient temperature with 3 barhydrogen. The catalyst is filtered off, the filtrate concentrated byevaporation and the residue purified through a silica gel column withmethylene chloride/methanol (9:1).

Yield: 16 mg of (4% of theory),

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=9:1)

C₂₇H₂₆N₄O₃

The following compound is prepared analogously to Example XIV:

-   (1)    1-acetoxy-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-6-nitro-2-indolinone    Prepared from    1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2-indolinone and    methyl 4-aminobenzoate without subsequent hydrogenation

ESI mass spectrum: m/z=472 [M−H⁻]

EXAMPLE XV

N-(2-dimethylamino-ethyl)-N-methylsulphonyl-4-nitroaniline

38.9 g of N-methylsulphonyl-4-nitroaniline are dissolved in 2.01 ofacetone, 51.9 g of 1-chloro-2-dimethylamino-ethane, 77.4 g of potassiumcarbonate and 5.0 g of sodium iodide added and the mixture is stirredfor a total of 4 days at 50° C., adding, after 12 hours, a further 25.9g of 1-chloro-2-dimethylamino-ethane, 49.8 g of potassium carbonate and5.0 g of sodium iodide in 500 ml of acetone and, after 36 hours, afurther 26.0 g of 1-chloro-2-dimethylamino-ethane, 50.0 g of potassiumcarbonate and 5.0 g of sodium iodide in 100 ml of acetone. After thistime the mixture is filtered and the filtrate is evaporated down. Theresidue is stirred with ether, suction filtered and dried at 40° C.

Yield: 25.3 g (49% of theory),

R_(f) value: 0.5 (silica gel, methylenechloride/methanol/ammonia=9:1:0.1)

C₁₁H₁₇N₃O₄S

ESI mass spectrum: m/z=288 [M+H⁺]

The following compound is prepared analogously to Example XV:

-   (1) N-carboxymethyl-N-methylsulphonyl-4-nitroaniline

EXAMPLE XVI

N-(dimethylaminocarbonyl-methyl)-N-methylsulphonyl-4-nitroaniline

7.0 g of N-carboxymethyl-N-methylsulphonyl-4-nitroaniline, 2.5 g ofdimethylamine hydrochloride, 8.1 g of TBTU and 3.9 g of HOBT aredissolved in 125 ml of dimethylformamide and at 0° C. 17.6 ml ofN-ethyl-diisopropylamine are added. The mixture is stirred for 4 hoursat ambient temperature, diluted with 11 water and the precipitate formedis suction filtered. After washing with water, ethanol and ether theresidue is dried at 70° C. in vacuo.

Yield: 5.3 g (69% of theory),

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

C₁₁H₁₅N₃O₅S

ESI mass spectrum: m/z=300 [M−H⁻]

The following compound is prepared analogously to Example XVI:

-   (1)    N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methyl-sulphonyl-4-nitroaniline

EXAMPLE XVII

N-(dimethylaminomethylcarbonyl)-N-methyl-4-nitro-aniline

1.8 g of dimethylamine hydrochloride and 5.5 g of potassium carbonateare placed in 80 ml of acetone and 4.2 g ofN-(2-bromomethylcarbonyl)-N-methyl-4-nitroaniline (prepared according toChem. Ber. 119, 2430 (1986)) are added in three batches at ambienttemperature. The mixture is stirred for 12 hours at ambient temperature.After this time the mixture is filtered and the filtrate is concentratedby evaporation. The residue is dissolved in ethyl acetate, washed twicewith water, dried over sodium sulphate and finally concentrated byrotary evaporation.

Yield: 2.8 g (79% of theory),

R_(f) value: 0.5 (silica gel, ethyl acetate/methanol=7:3)

Melting point: 121-122° C.

EXAMPLE XVIII

4-(piperidin-1-yl-methyl)-nitrobenzene

40.0 g of 4-nitrobenzylbromide are in 500 ml of methylene chloridedissolved, 51.5 ml of triethylamine are added and 18.3 ml of piperidineare carefully added dropwise. After the end of the exothermic reactionthe mixture is refluxed for a further 30 minutes. After cooling it iswashed with water and the organic phase is dried over sodium sulphate.Finally, the organic phase is evaporated down.

Yield: 36.3 g (89% of theory),

R_(f) value: 0.6 (silica gel, methylene chloride/methanol=9:1)

C₁₂H₁₆N₂O₂

Mass spectrum: m/z=221 [M⁺]

The following compounds are prepared analogously to Example XVIII:

-   (1) 4-[(N-benzyl-N-methyl-amino)-methyl]-nitrobenzene-   (2) 3-(dimethylaminomethyl)-nitrobenzene-   (3) 4-(dimethylaminomethyl)-nitrobenzene-   (4) 4-(2-dimethylamino-ethyl)-nitrobenzene-   (5) 4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-nitrobenzene-   (6) 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-nitrobenzene-   (7) 4-(pyrrolidin-1-yl-methyl)-nitrobenzene

EXAMPLE IXX

4-(4-methyl-piperazin-1-yl)-nitrobenzene

31.5 g of 4-chloro-1-nitrobenzene and 44.4 ml of 1-methyl-piperazine arecombined and stirred for 18 hours at 90° C. Then the solution is pouredonto ice water and the precipitate formed is suction filtered, washedwith water and recrystallised from ethanol/water (1:1). The residue isdried in vacuo at 75° C.

Yield: 44.0 g (99% of theory),

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

Melting point: 108-112° C.

The following compounds are prepared analogously to Example IX:

-   (1) N-(2-dimethylaminoethyl)-N-methyl-4-nitroaniline    Prepared from 1-fluoro-4-nitrobenzene and    1-dimethylamino-2-methylamino-ethane-   (2) N-(3-dimethylaminopropyl)-N-methyl-4-nitroaniline    Prepared from 1-fluoro-4-nitrobenzene and    1-dimethylamino-3-methylamino-propane

EXAMPLE XX

4-[N-acetyl-(2-dimethylaminoethyl)-amino]-nitrobenzene

3.6 g of 4-(2-dimethylamino-ethylamino)-nitrobenzene (according toGabbay et al., J. Am. Chem. Soc. 91, 5136 (1969)) are dissolved in 50 mlof methylene chloride and 5.0 ml of triethylamine are added. To thismixture 1.3 ml of acetylchloride are slowly added dropwise at ambienttemperature and the mixture is stirred for 2 hours at ambienttemperature. After this time a further 5.0 ml of triethylamine and 1.3ml of acetylchloride are added and the mixture is refluxed for a further2 hours. The solvent is eliminated in vacuo, the residue is taken up inethyl acetate and the organic phase is extracted twice with water. Afterdrying over magnesium sulphate the solvent is eliminated and the residueis dried in vacuo.

Yield: 2.0 g (45% of theory),

R_(f) value: 0.55 (silica gel, methylenechloride/methanol/ammonia=9:1:0.1)

C₁₂H₁₇N₃O₃

ESI mass spectrum: m/z=252 [M+H⁺]

The following compounds are prepared analogously to Example XX:

-   (1) 4-[N-acetyl-N-(3-dimethylaminopropyl)-amino]-nitrobenzene    Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene and    acetylchloride-   (2) 4-[N-propionyl-N-(2-dimethylaminoethyl)-amino]-nitrobenzene    Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and    propionylchloride-   (3) 4-[N-propionyl-N-(3-dimethylaminopropyl)-amino]-nitrobenzene    Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene and    propionylchloride

EXAMPLE XXI

4-nitro-N,N-dimethylbenzamide

10.0 g of 4-nitrobenzoic acid, 8.4 g of dimethylamine hydrochloride and18.3 g of TBTU are placed in 50 ml of dimethylformamide, 78.4 ml ofN-ethyl-diisopropylamine are added at ambient temperature and themixture is stirred for 15 hours at ambient temperature. After this timethe mixture is combined with water and extracted with ethyl acetate. Theorganic phase is again extracted with water and with 1N hydrochloricacid, dried over sodium sulphate and concentrated by evaporation. Theproduct is recrystallised from ether.

Yield: 5.6 g (48% of theory),

R_(f) value: 0.6 (silica gel, methylene chloride/methanol=9:1)

Melting point: 61-63° C.

The following compound is prepared analogously to Example XXI:

-   (1) 4-(piperidin-1-yl-carbonyl)-nitrobenzene    Prepared from 4-nitrobenzoic acid and piperidine

EXAMPLE XXII

4-(piperidin-1-yl-methyl)-aniline

37.0 g of 4-(piperidin-1-yl-methyl)-nitrobenzene are dissolved in 300 mlof methanol, 8.0 g of Raney nickel are added and the mixture ishydrogenated for 1 hour 25 minutes with 3 bar hydrogen at ambienttemperature. The catalyst is filtered off and the filtrate isconcentrated by evaporation.

Yield: 24.0 g (75% of theory),

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=9:1)

C₁₂H₁₈N₂

ESI mass spectrum: m/z=191 [M+H⁺]

The following compounds are prepared analogously to Example XXII:

-   (1) 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline-   (2) N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine-   (3) 3-(dimethylaminomethyl)-aniline-   (4) 4-(dimethylaminomethyl)-aniline-   (5) 4-(2-dimethylamino-ethyl)-aniline-   (6) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine-   (7) 4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-aniline-   (8)    N-(dimethylaminocarbonylmethyl)-N-methylsulphonyl-p-phenylenediamine-   (9) 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline-   (10)    N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methyl-sulphonyl-p-phenylenediamine-   (11) 4-(pyrrolidin-1-yl-methyl)-aniline-   (12) 4-(4-methyl-piperazin-1-yl)-aniline-   (13) N-(2-dimethylaminoethyl)-N-methyl-p-phenylenediamine-   (14) N-(3-dimethylaminopropyl)-N-methyl-p-phenylenediamine-   (15) N-acetyl-N-(2-dimethylaminoethyl)-p-phenylenediamine-   (16) N-acetyl-N-(3-dimethylaminopropyl)-p-phenylenediamine-   (17) N-propionyl-N-(2-dimethylaminoethyl)-p-phenylenediamine-   (18) N-propionyl-N-(3-dimethylaminopropyl)-p-phenylenediamine-   (19) N-methylsulphonyl-p-phenylenediamine-   (20) 4-amino-N,N-dimethylbenzamide-   (21) 4-(piperidin-1-yl-carbonyl)-aniline-   (22) 4-tetrazol-5-yl-aniline

Preparation of the final compounds:

EXAMPLE 1

3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone

700 mg of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-di-methoxy-2-indolinoneand 300 mg of 4-(piperidin-1-yl-methyl)-aniline are suspended in 3.0 mlof dimethylformamide and stirred for 2 hours at 110° C. After cooling1.0 ml of piperidine is added and the mixture is stirred for 3 hours atambient temperature, combined with water and the precipitate formed issuction filtered. The precipitate is separated through a silica gelcolumn with methylene chloride/methanol/ammonia (10:1:0.01), stirredwith ether, suction filtered and dried at 100° C.

Yield: 300 mg of (55% of theory),

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=5:1)

C₂₉H₂₉N₃O₄

Mass spectrum: m/z=469 [M⁺]

The following compounds are prepared analogously to Example 1:

-   (1)    3-(Z)-[1-(4-methoxy-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and p-anisidine

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=10:1)

C₂₄H₂₂N₂O₄

Mass spectrum: m/z=402 [M⁺]

-   (2)    3-(Z)-[1-(4-chloro-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-chloroaniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₃H₁₉CN₁₂O₃

Mass spectrum: m/z=406/408 [M₊]

-   (3)    3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₃₂H₃₁N₃O₃

Mass spectrum: m/z=505 [M⁺]

-   (4)    3-(Z)-(1-{4-[N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1)

C₂₈H₃₂N₄O₅S

Mass spectrum: m/z=536 [M⁺]

-   (5)    3-(Z)-{1-[3-(dimethylamino-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 3-(dimethylaminomethyl)-aniline

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=5:1)

C₂₆H₂₇N₃O₃

Mass spectrum: m/z=429 [M⁺]

-   (6)    3-(Z)-{1-(4-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(dimethylaminomethyl)-aniline

R_(f) value: 0.5 (silica gel, methylenechloride/methanol/ammonia=10:1:1)

C₂₆H₂₇N₃O₃

Mass spectrum: m/z=429 [M⁺]

-   (7)    3-(Z)-{1-[4-(2-dimethylamino-ethyl)-anilino]-1-phenyl-methylidene-}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(2-dimethylamino-ethyl)-aniline

R_(f) value: 0.6 (silica gel, methylenechloride/methanol/ammonia=5:1:0.01)

C₂₇H₂₉N₃O₃

Mass spectrum: m/z=443 [M⁺]

-   (8)    3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₈H₃₀N₄O₄

Mass spectrum: m/z=486 [M⁺]

-   (9)    3-(Z)-{1-[4-(1H-imidazol-4-yl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(1H-imidazo-4-yl)-aniline (prepared according to Chem. Pharm.    bull. 38, 1803 (1990))

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₆H₂₂N₄O₃

ESI mass spectrum: m/z=439 [M+H⁺]

-   (10)    3-(Z)-(1-{4-[2-(4-carboxyethyl-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₃₃H₃₇N₃O₅

ESI mass spectrum: m/z=554 [M−H⁻]

-   (11)    3-(Z)-(1-{4-[N-(dimethylaminocarbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and    N-(dimethylaminocarbonylmethyl)-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₈H₃₀N₄O₆S

Mass spectrum: m/z=550 [M⁺]

-   (12)    3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and ethyl 4-aminobenzoate

R_(f) value: 0.5 (silica gel, methylene chloride/ethanol=20:1)

C₂₆H₂₄N₂O₅

Mass spectrum: m/z=444 [M⁺]

-   (13)    3-(Z)-(1-{4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline

R_(f) value: 0.5 (silica gel, methylenechloride/methanol/ammonia=10:1:0.01)

C₃₁H₃₅N₃O₃

Mass spectrum: m/z=497 [M⁺]

-   (14)    3-(Z)-[1-(4-{N-[(2-dimethylamino-ethylamino)-carbonyl-methyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and    N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.3 (silica gel, methylene chloride/methanol=4:1)

C₃₀H₃₅N₅O₆S

Mass spectrum: m/z=593 [M⁺]

-   (15)    3-(Z)-{1-[4-(pyrrolidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(pyrrolidin-1-yl-methyl)-aniline

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=5:1)

C₂₈H₂₉N₃O₃

Mass spectrum: m/z=455 [M⁺]

-   (16)    3-(Z)-{1-[4-(4-methyl-piperazin-1-yl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(4-methyl-piperazin-1-yl)-aniline

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=10:1)

C₂₈H₃₀N₄O₃

Mass spectrum: m/z=470 [M⁺]

-   (17)    3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylamino-ethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-acetyl-N-(2-dimethylamino-ethyl)-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=9:1)

C₂₉H₃₂N₄O₄

ESI mass spectrum: m/z=499 [M−H⁻]

-   (18)    3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylamino-propyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamine

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=10:1)

C₃₀H₃₄N₄O₄

ESI mass spectrum: m/z=515 [M+H⁺]

-   (19)    3-(Z)-(1-{4-[N-propionyl-N-(2-dimethylamino-ethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-propionyl-N-(2-dimethylamino-ethyl)-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=9:1)

C₃₀H₃₄N₄O₄

ESI mass spectrum: m/z=515 [M+H⁺]

-   (20)    3-(Z)-(1-{4-[N-propionyl-N-(3-dimethylamino-propyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-propionyl-N-(3-dimethylamino-propyl)-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₃₁H₃₆N₄O₄

ESI mass spectrum: m/z=529 [M+H⁺]

-   (21)    3-(Z)-[1-(4-aminocarbonyl-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-aminobenzamide

R_(f) value: 0.4 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₄H₂₁N₃O₄

ESI mass spectrum: m/z=414 [M−H⁻]

-   (22)    3-(Z)-[1-(4-dimethylaminocarbonyl-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-amino-dimethylbenzamide

R_(f) value: 0.4 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₆H₂₅N₃O₄

ESI mass spectrum: m/z=442 [M−H⁻]

-   (23)    3-(Z)-{1-[4-(piperidin-1-yl-carbonyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(piperidin-1-yl-carbonyl)-aniline

R_(f) value: 0.4 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₉H₂₉N₃O₄

ESI mass spectrum: m/z=482 [M−H⁻]

-   (24)    3-(Z)-[1-(4-ethoxycarbonylmethyl-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and ethyl 4-aminophenylacetate

R_(f) value: 0.5 (silica gel, petroleum ether/ethylacetate/ethanol=7:2:1)

C₂₂₇H₂₆N₂O₅

ESI mass spectrum: m/z=457 [M−H⁻]

-   (25)    3-(Z)-{1-[4-(tetrazol-5-yl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-tetrazol-5-yl-aniline

R_(f) value: 0.4 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₄H₂₀N₆O₃

ESI mass spectrum: m/z=439 [M−H⁻]

-   (26)    3-(Z)-[1-anilino-1-(3-cyanophenyl)-methylidene]-5,6-di-methoxy-2-indolinone    Prepared from    1-acetyl-3-[1-chloro-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-indolinone    and aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₄H₁₉N₃O₃

ESI mass spectrum: m/z=396 [M−H⁻]

-   (27)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(piperidin-1-yl-methyl)-aniline

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=5:1)

C₂₅H₃₁N₃O₃

Mass spectrum: m/z=421 [M⁺]

-   (28)    3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-(dimethylaminomethyl)-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=5:1)

C₂₂H₂₇N₃O₃

Mass spectrum: m/z=381 [M⁺]

-   (29)    3-(Z)-(1-anilino-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and aniline

R_(f) value: 0.3 (silica gel, methylene chloride/methanol=20:1)

C₁₉H₂₀N₂O₃

Mass spectrum: m/z=324 [M⁺]

-   (30)    3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.4 (Alox, methylene chloride/ethanol=20:1)

-   C₂₄H₃₂N₄O₅S

ESI mass spectrum: m/z=489 [M+H⁺]

-   (31)    3-(Z)-(1-{4-[N-(2-dimethylaminoethyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-(2-dimethylaminoethyl)-N-methyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=5:1)

C₂₄H₃₂N₄O₃

ESI mass spectrum: m/z=425 [M+H⁺]

-   (32)    3-(Z)-(1-{4-[N-(3-dimethylaminopropyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-(3-dimethylaminopropyl)-N-methyl-p-phenylenediamine

R_(f) value: 0.6 (silica gel, methylenechloride/methanol/ammonia=5:1:0.01)

C₂₅H₃₄N₄O₃

ESI mass spectrum: m/z=439 [M+H⁺]

-   (33)    3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylaminopropyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamine

R_(f) value: 0.4 (Alox, methylene chloride/ethanol=25:1)

C₂₆H₃₄N₄O₄

ESI mass spectrum: m/z=467 [M+H⁺]

-   (34)    3-(Z)-{1-[4-(N-methylsulphonylamino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₁H₂₅N₃O₅S

ESI mass spectrum: m/z=430 [M−H⁻]

-   (35)    3-(Z)-{1-[4-(N-acetylamino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-acetyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=9:1)

C₂₂H₂₅N₃O₄

ESI mass spectrum: m/z=394 [M−H⁻]

-   (36)    3-(Z)-(1-{4-[N-(dimethylaminocarbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and    N-(dimethylaminocarbonylmethyl)-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₄H₃₀N₄O₆S

Mass spectrum: m/z=502 [M⁺]

-   (37)    3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and ethyl 4-aminobenzoate

R_(f) value: 0.6 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₂H₂₄N₂O₅

ESI mass spectrum: m/z=395 [M−H⁻]

-   (38)    3-(Z)-[1-(4-aminocarbonyl-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-aminobenzamide

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

-   C₂₀H₂₁N₃O₄-   Mass spectrum: m/z=367 [M⁺]-   (39)    3-(Z)-[1-(4-dimethylaminocarbonyl-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-amino-dimethylbenzamide

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₂H₂₅N₃O₄

ESI mass spectrum: m/z=394 [M−H⁻]

-   (40)    3-(Z)-{1-[4-(ethoxycarbonylmethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and ethyl 4-aminophenylacetate

R_(f) value: 0.4 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₃H₂₆N₂O₅

Mass spectrum: m/z=410 [M⁺]

-   (41)    3-(Z)-{1-[4-(tetrazol-5-yl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and 4-tetrazol-5-yl-aniline

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

C₂₀H₂₀N₆O₃

ESI mass spectrum: m/z=391 [M−H⁻]

-   (42)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-methylenedioxy-2-indolinone    Prepared from    3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone    and 4-(piperidin-1-yl-methyl)-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=5:1)

C₂₈H₂₇N₃O₃

Mass spectrum: m/z=453 [M⁺]

-   (43)    3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-methylenedioxy-2-indolinone    Prepared from    3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone    and 4-(dimethylaminomethyl)-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=5:1)

C₂₅H₂₃N₃O₃

Mass spectrum: m/z=413 [M⁺]

-   (44)    3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene}-5,6-methylenedioxy-2-indolinone    Prepared from    3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone    and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=5:1)

C₃₁H₂₇N₃O₃

Mass spectrum: m/z=489 [M⁺]

-   (45)    3-(Z)-(1-{4-[N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone    Prepared from    3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone    and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.6 (silica gel, methylene chloride/methanol=5:1)

C₂₇H₂₈N₄O₅S

Mass spectrum: m/z=520 [M⁺]

-   (46)    3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-methylenedioxy-2-indolinone    Prepared from    3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone    and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine

R_(f) value: 0.3 (silica gel, methylene chloride/methanol=5:1)

C₂₇H₂₆N₄O₄

Mass spectrum: m/z=470 [M⁺]

-   (47)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-methoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone    and 4-(piperidin-1-yl-methyl)-aniline

R_(f) value: 0.4 (aluminium oxide, toluene/ethylacetate/methanol=4:2:0.25)

C₂₈H₂₉N₃O₂

Mass spectrum: m/z=439 [M⁺]

-   (48)    3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-6-methoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone    and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline

R_(f) value: 0.5 (aluminium oxide, toluene/ethylacetate/ethanol=4:2:0.25)

C₃₁H₂₉N₃O₂

Mass spectrum: m/z=475 [M⁺]

-   (49)    3-(Z)-{1-[3-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene}-6-methoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone    and 3-(dimethylaminomethyl)-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=5:1)

C₂₅H₂₅N₃O₂

Mass spectrum: m/z=399 [M⁺]

-   (50)    3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone    and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=5:1)

C₂₄H₃₀N₄O₄

Mass spectrum: m/z=438 [M⁺]

-   (51)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone    and 4-(piperidin-1-yl-methyl)-aniline

R_(f) value: 0.4 (aluminium oxide, toluene/ethyl acetate=2:1)

C₃₁H₃₅N₃O₃

ESI mass spectrum: m/z=498 [M+H⁺]

-   (52)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-trifluoromethyl-2-indolinone    Prepared from    1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone    and 4-(piperidin-1-yl-methyl)-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₈H₂₆F₃N₃O

ESI mass spectrum: m/z=476 [M−H⁻]

-   (53)    3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone    Prepared from    1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone    and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₇H₂₇F₃N₄O₃S

ESI mass spectrum: m/z=543 [M−H⁻]

-   (54)    3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-6-trifluoromethyl-2-indolinone    Prepared from    1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone    and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=10:1)

C₂₇H₂₅F₃N₄O₂

ESI mass spectrum: m/z=493 [M−H⁻]

-   (55)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-phenyl-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and    4-(piperidin-1-yl-methyl)-aniline

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

C₃₃H₃₁N₃O

ESI mass spectrum: m/z=486 [M+H⁺]

-   (56)    3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-6-phenyl-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and    4-[(N-benzyl-N-methyl-amino)-methyl]-aniline

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

C₃₃H₃₁N₃O

ESI mass spectrum: m/z=486 [M+H⁺]

-   (57)    3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-6-phenyl-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and    N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=9:1)

C₃₂H₃₂N₄O₃S

ESI mass spectrum: m/z=553 [M+H⁺]

-   (58)    3-(Z)-{1-[3-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene}-6-phenyl-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and    3-(dimethylaminomethyl)-aniline

R_(f) value: 0.55 (silica gel, methylene chloride/methanol=10:1)

C₃₀H₂₇N₃O

ESI mass spectrum: m/z=446 [M+H⁺]

-   (59)    3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-6-phenyl-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and    N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

C₃₂H₃₀N₄O₂

Mass spectrum: m/z=502 [M⁺]

-   (60)    3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-(2-tolyl)-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone    and 4-(piperidin-1-yl-methyl)-aniline

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=9:1)

C₃₄H₃₃N₃O

ESI mass spectrum: m/z=500 [M+H⁺]

-   (61)    3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene}-6-(2-tolyl)-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone    and 4-(dimethylaminomethyl)-aniline

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

C₃₁H₂₉N₃O

Mass spectrum: m/z=459 [M⁺]

-   (62)    3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylidene]-6-(2-tolyl)-2-indolinone    Prepared from    1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone    and ethyl 4-aminobenzoate

R_(f) value: 0.5 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₃₁H₂₆N₂O₃

Mass spectrum: m/z=474 [M⁺]

EXAMPLE 2

3-(Z)-(1-{4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone

0.4 g of3-(Z)-(1-{4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinoneare dissolved in 8.0 ml of ethanol and 2.0 ml of 1N sodium hydroxidesolution are added. The mixture is stirred for 1 hour at 50° C. 2.0 mlof 1N HCl are added to the clear solution and the precipitate formed issuction filtered. The precipitate is washed with water and ethanol anddried in vacuo at 100° C.

Yield: 0.2 g (64% of theory),

R_(f) value: 0.2 (silica gel, methylene chloride/methanol=2:1)

C₃₁H₃₃N₃O₅

ESI mass spectrum: m/z=526 [M−H⁻]

The following compounds are prepared analogously to Example 2:

-   (1)    3-(Z)-[1-(4-carboxy-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone    Prepared from    3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=10:1)

C₂₄H₂₀N₂O₅

ESI mass spectrum: m/z=415 [M−H—W

-   (2)    3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    3-(Z)-{1-[4-(ethoxycarbonylmethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone

R_(f) value: 0.1 (silica gel, petroleum ether/ethylacetate/ethanol=7:2:1)

C₂₅H₂₂N₂O₅

ESI mass spectrum: m/z=429 [M−H⁻]

-   (3)    3-(Z)-[1-(4-carboxy-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone    Prepared from    3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone

R_(f) value: 0.4 (silica gel, methylene chloride/methanol=9:1)

C₂₀H₂₀N₂O₅

ESI mass spectrum: m/z=367 [M−H⁻]

-   (4)    3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    3-(Z)-{1-[4-(ethoxycarbonylmethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone

R_(f) value: 0.4 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₁H₂₂N₂O₅

ESI mass spectrum: m/z=381 [M−H⁻]

-   (5)    3-(Z)-[1-(4-carboxy-anilino)-1-phenyl-methylidene]-6-ureido-2-indolinone    Prepared from    3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-6-ureido-2-indolinone

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=4:1)

C₂₃H₁₈N₄O₄

ESI mass spectrum: m/z=413 [M−H⁻]

EXAMPLE 3

3-(Z)-(1-{4-(2-{4-dimethylcarbamoyl-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone

0.2 g of3-(Z)-(1-(4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinoneare dissolved in 5.0 ml of dimethylformamide and 0.2 g of TBTU, 0.1 g ofHOBT and 0.5 ml of triethylamine are added. Finally 0.2 g ofdimethylamine hydrochloride are added and the mixture is stirred for 2hours at ambient temperature. The solvent is eliminated and the residueis stirred with water, suction filtered and washed with isopropanol andether. The residue is dried in vacuo at 100° C.

Yield: 0.2 g (95% of theory),

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₃₃H₃₈N₄O₄

Mass spectrum: m/z=554 [M⁺]

The following compounds are prepared analogously to Example 3:

-   (1)    3-(Z)-{1-[4-(aminocarbonylmethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    and N-hydroxy-succinimide-ammonium salt

R_(f) value: 0.4 (silica gel, petroleum ether/ethylacetate/ethanol=4:2:1)

C₂₅H₂₃N₃O₄

ESI mass spectrum: m/z=428 [M−H⁻]

-   (2)    3-(Z)-{1-[4-(dimethylaminocarbonylmethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone    and dimethylamine-hydrochloride

R_(f) value: 0.45 (silica gel, petroleum ether/ethylacetate/ethanol=4:2:1)

C₂₇H₂₇N₃O₄

ESI mass spectrum: m/z=456 [M−H⁻]

-   (3)    3-(Z)-{1-[4-(aminocarbonylmethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    and N-hydroxy-succinimide-ammonium salt

R_(f) value: 0.45 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₁H₂₃N₃O₄

ESI mass spectrum: m/z=380 [M−H⁻]

-   (4)    3-(Z)-{1-[4-(dimethylaminocarbonylmethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone    and dimethylamine-hydrochloride

R_(f) value: 0.7 (silica gel, toluene/ethyl acetate/ethanol=4:2:1)

C₂₃H₂₇N₃O₄

ESI mass spectrum: m/z=408 [M−H⁻]

EXAMPLE 4

6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone

11.2 g of3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-nitro-2-indolinoneare dissolved in 120 ml of methanol and 60 ml of methylene chloride, 1.1g of palladium on carbon (10%) are added and the mixture is hydrogenatedfor 2 hours 45 minutes at ambient temperature with 3 bar hydrogen. Thecatalyst is filtered off, the filtrate is concentrated by evaporationand the residue is purified through a silica gel column with methylenechloride/methanol (4:1).

Yield: 5.2 g (52% of theory),

R_(f) value: 0.25 (silica gel, methylene chloride/methanol=4:1)

C₂₇H₂₈N₄O

ESI mass spectrum: m/z=425 [M+H⁺]

The following compound is prepared analogously to Example 4:

-   (1)    6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-2-indolinone    Prepared from    1-acetoxy-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-6-nitro-2-indolinone

R_(f) value: 0.74 (silica gel, methylene chloride/methanol=4:1)

C₂₃H₁₉N₃O₃

ESI mass spectrum: m/z=384 [M−H⁻]

EXAMPLE 5

3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-6-ureido-2-indolinone

560 mg of6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-2-indolinone,236 mg of potassium cyanate and 3.8 ml of glacial acetic acid aredissolved in 20 ml of ethanol and refluxed for 1 hour. After this timethe solvent is evaporated, the residue is taken up in methylenechloride, washed with water and dried over sodium sulphate. Afterevaporation, the product is dried in the desiccator.

Yield: 280 mg of (45% of theory),

R_(f) value: 0.25 (silica gel, ethylacetate/cyclohexane/methanol=4.5:4.5:1)

C₂₄H₂₀N₄O₄

ESI mass spectrum: m/z=427 [M−H⁻]

EXAMPLE 6

3-(Z)-[1-anilino-1-(3-aminomethyl-phenyl)-methylidene]-5,6-di-methoxy-2-indolinone

0.8 g of3-(Z)-[1-anilino-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-indolinoneare dissolved in 50 ml of methanolic ammonia and 30 ml of methylenechloride are added. After the addition of 500 mg of Raney nickel themixture is hydrogenated for 2 hours at ambient temperature at a pressureof 50 psi. After the end of the reaction the catalyst is filtered offand the filtrate is concentrated by evaporation. The residue isseparated over a silica gel column with methylene chloride/methanol(5:1) as eluant. The product is suspended in 3 ml of dioxane, 0.4 ml of1N hydrochloric acid are added and the solution formed is concentratedby evaporation after 10 minutes' stirring at ambient temperature. Theresidue thus obtained is triturated with ether, suction filtered anddried in vacuo at 80° C.

Yield: 0.1 g (14% of theory),

R_(f) value: 0.7 (silica gel, methylenechloride/methanol/ammonia=5:1:0.01)

C₂₄H₂₃N₃O₃

ESI mass spectrum: m/z=402 [M+H⁺]

EXAMPLE 7

6-benzoylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone

0.4 g of6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinoneare dissolved in 25 ml of methylene chloride, 12.5 ml of pyridine areadded and at ambient temperature 0.1 ml of benzoylchloride are addeddropwise. The reaction mixture is stirred for 12 hours at ambienttemperature, concentrated by evaporation and purified through a silicagel column with methylene chloride/methanol=4:1 as eluant.

Yield: 160 mg of (32% of theory),

R_(f) value: 0.3 (silica gel, methylene chloride/methanol=9:1)

C₃₄H₃₂N₄O₂

ESI mass spectrum: m/z=529 [M+H⁺]

The following compounds are prepared analogously to Example 7:

-   (1)    6-acetylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone

Prepared from6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinoneand acetylchloride

R_(f) value: 0.48 (silica gel, methylene chloride/methanol=4:1)

C₂₉H₃₀N₄O₂

ESI mass spectrum: m/z=467 [M+H⁺]

-   (2)    6-(2-phenylacetylamino)-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    Prepared from    6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    and phenylacetic acid chloride

R_(f) value: 0.67 (silica gel, methylene chloride/methanol=4:1)

C₃₅H₃₄N₄O₂

ESI mass spectrum: m/z=543 [M+H⁺]

-   (3)    6-methanesulphonylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    Prepared from    6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    and methanesulphonylchloride

R_(f) value: 0.56 (silica gel, methylene chloride/methanol=4:1)

C₂₈H₃₀N₄O₃S

ESI mass spectrum: m/z=503 [M+H⁺]

-   (4)    6-benzenesulphonylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    Prepared from    6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    and benzenesulphonyl chloride

R_(f) value: 0.53 (silica gel, methylene chloride/methanol=4:1)

C₃₃H₃₂N₄O₃S

ESI mass spectrum: m/z=565 [M+H⁺]

-   (5)    3-(Z)-{1-anilino-1-[3-(acetylaminomethyl)-phenyl]-methylidene}-5,6-dimethoxy-2-indolinone    Prepared from    3-(Z)-[1-anilino-1-(3-aminomethyl-phenyl)-methylidene]-5,6-dimethoxy-2-indolinone    and acetic anhydride

R_(f) value: 0.5 (silica gel, methylene chloride/methanol=10:1)

C₂₆H₂₅N₃O₄

ESI mass spectrum: m/z=442 [M−H⁻]

EXAMPLE 8

6-methylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinoneand

6-dimethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone

0.1 ml of formaldehyde solution (37%) are dissolved in 20 ml ofmethanol, 0.5 g of6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinoneare added and the mixture is stirred for 1 hour at ambient temperature.A precipitate is formed which is brought into solution by the additionof 5 ml of methylene chloride. To this mixture are added 75 mg of sodiumcyanoborohydride and the mixture is stirred for 12 hours at ambienttemperature. After this time 5 ml of conc. HCl are added, the solvent issubstantially eliminated, the residue taken up in water and made basicwith sodium hydroxide solution. The aqueous phase is extracted withmethylene chloride, dried over sodium sulphate, concentrated byevaporation and purified through a silica gel column with methylenechloride/methanol (4:1).

Yield: 70 mg of (13% of theory)6-methylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone,

R_(f) value: 0.64 (silica gel, methylene chloride/methanol=4:1)

C₂₈H₃₀N₄O

Mass spectrum: m/z=438 [M⁺]

35 mg of (6% of theory)6-dimethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone,

R_(f) value: 0.58 (silica gel, methylene chloride/methanol=4:1)

C₂₉H₃₄N₄O

ESI mass spectrum: m/z=453 [M+H⁺]

EXAMPLE 9

3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-(pyrrol-1-yl)-2-indolinone

0.5 g of6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinoneare dissolved in 20 ml of glacial acetic acid and 0.2 ml of2,5-dimethoxytetrahydrofuran are added. The mixture is refluxed for 1hour, concentrated by evaporation and the residue is taken up in 20 mlof water. After another 2 hours' stirring the mixture is made basic with1N sodium hydroxide solution, the aqueous phase is extracted withmethylene chloride and the organic phase is dried over sodium sulphate.After elimination of the solvent the residue is purified through asilica gel column with methylene chloride/methanol (4:1) as eluant.

Yield: 200 mg of (36% of theory),

R_(f) value: 0.73 (silica gel, methylene chloride/methanol=4:1)

C₃₁H₃₀N₄O

ESI mass spectrum: m/z=475 [M+H⁺]

EXAMPLE 10

3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-6-(pyrrolidin-1-yl)-2-indolinone

0.3 g of6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinoneare dissolved in 10 ml of dimethylformamide and 180 mg of potassiumcarbonate are added. 0.1 ml of 1,4-dibromobutane (dissolved in 1.0 ml ofdimethylformamide) is added dropwise at ambient temperature and thereaction mixture is stirred for 12 hours at 80° C. After cooling themixture is poured onto water and the precipitate formed is filtered off.

Yield: 110 mg of (33.% of theory),

R_(f) value: 0.41 (silica gel, methylene chloride/methanol=9:1)

C₃₁H₃₄N₄O

ESI mass spectrum: m/z=479 [M+H⁺]

The following compound is prepared analogously to Example 10:

-   (1)    6-methoxycarbonylmethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    Prepared from    6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone    and methyl bromoacetate

Yield: 230 mg of (28% of theory),

R_(f) value: 0.36 (silica gel, methylene chloride/methanol=9:1)

C₃₀H₃₂N₄O₃

ESI mass spectrum: m/z=497 [M+H⁺]

EXAMPLE 11

6-carboxymethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone

180 mg of6-methoxycarbonylmethylamino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinoneare placed in 10 ml of methanol, 1.0 ml of 1N sodium hydroxide solutionare added and the mixture is stirred for 1 hour at 40° C. After coolingit is neutralised with 1.0 ml of 1N hydrochloric acid and the solvent iseliminated. The residue is dissolved in methylene chloride and a littlemethanol and dried over sodium sulphate.

Yield: 76 mg of (44% of theory),

R_(f) value: 0.05 (silica gel, methylene chloride/methanol=9:1)

C₂₉H₃₀N₄O₃

ESI mass spectrum: m/z=483 [M+H⁺]

The following compounds may be prepared analogously to the precedingExamples:

-   (1)    3-(Z)-(1-anilino-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (2)    3-(Z)-[1-(4-nitro-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone-   (3)    3-(Z)-1-[(4-fluoro-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone-   (4)    3-(Z)-[1-(4-bromo-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone-   (5)    3-(Z)-[1-(4-iodo-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone-   (6)    3-(Z)-[1-(4-cyano-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone-   (7)    3-(Z)-[1-(4-ethoxy-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone-   (8)    3-(Z)-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone-   (9)    3-(Z)-[1-(4-methyl-anilino)-1-phenyl-methylidene]-5,6-di-methoxy-2-indolinone-   (10)    3-(Z)-[1-(4-methylmercapto-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone-   (11)    3-(Z)-[1-(4-aminomethyl-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone-   (12)    3-(Z)-{1-[4-(methylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (13)    3-(Z)-{1-[4-(isopropylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (14)    3-(Z)-{1-[4-(phenylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (15)    3-(Z)-{1-[4-(ethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (16)    3-(Z)-{1-[4-(propylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (17)    3-(Z)-{1-[4-(butylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (18)    3-(Z)-{1-[4-(isobutylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (19)    3-(Z)-{1-[4-(cyclohexylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (20)    3-(Z)-{1-[4-(benzylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (21)    3-(Z)-(1-{4-[(N-ethyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (22)    3-(Z)-{1-[4-(diethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (23)    3-(Z)-(1-{4-[(N-methyl-N-propyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (24)    3-(Z)-(1-{4-[(N-isopropyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (25)    3-(Z)-(1-{4-[(N-ethyl-N-propyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (26)    3-(Z)-(1-{4-[(N-ethyl-N-isopropyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (27)    3-(Z)-{1-[4-(dipropylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (28)    3-(Z)-{1-[4-(diisopropylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (29)    3-(Z)-(1-{4-[(N-benzyl-N-ethyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (30)    3-(Z)-{1-[4-(dibenzylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (31)    3-(Z)-{1-[4-(3,6-dihydro-2H-pyridine-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (32)    3-(Z)-{1-[4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (33)    3-(Z)-{1-[4-(azepan-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (34)    3-(Z)-{1-[4-(piperazin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (35)    3-(Z)-{1-[4-(morpholin-4-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (36)    3-(Z)-{1-[4-(thiomorpholin-4-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (37)    3-(Z)-{1-[4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (38)    3-(Z)-{1-[4-(acetylamino-methyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (39)    3-(Z)-{1-[4-(2-amino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (40)    3-(Z)-{1-[4-(2-methylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (41)    3-(Z)-{1-[4-(2-ethylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (42)    3-(Z)-{1-[4-(2-diethylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (43)    3-(Z)-{1-[4-(2-piperidin-1-yl-ethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (44)    3-(Z)-{1-[4-(2-acetylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (45)    3-(Z)-{1-[4-(3-amino-propyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (46)    3-(Z)-{1-[4-(3-dimethylamino-propyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (47)    3-(Z)-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (48)    3-(Z)-{1-[4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (49)    3-(Z)-{1-[4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (50)    3-(Z)-{1-[4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (51)    3-(Z)-(1-{4-[N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (52)    3-(Z)-(1-{4-[N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (53)    3-(Z)-(1-{4-[N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (54)    3-(Z)-(1-{4-[N-(2-amino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (55)    3-(Z)-{1-(4-[N-(2-methylamino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (56)    3-(Z)-(1-{4-[N-(2-diethylamino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (57)    3-(Z)-(1-{4-[N-acetyl-N-(2-aminoethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (58)    3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-ethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (59)    3-(Z)-(1-{4-[N-acetyl-N-(3-amino-propyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (60)    3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-propyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (61)    3-(Z)-(1-{4-[N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (62)    3-(Z)-(1-{4-[N-acetyl-N-(aminocarbonylmethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (63)    3-(Z)-(1-{4-[N-acetyl-N-(dimethylaminocarbonylmethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (64)    3-(Z)-(1-{4-[N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (65)    3-(Z)-(1-{4-[N-methyl-N-(aminocarbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (66)    3-(Z)-(1-{4-[N-methyl-N-(methylaminocarbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (67)    3-(Z)-(1-{4-[N-methyl-N-(dimethylaminocarbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (68)    3-(Z)-(1-{4-[N-methyl-N-(piperidin-1-yl-carbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (69)    3-(Z)-(1-{4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (70)    3-(Z)-(1-{4-[N-(2-methylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (71)    3-(Z)-(1-{4-[N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (72)    3-(Z)-(1-{4-[N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (73)    3-(Z)-(1-{4-[N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (74)    3-(Z)-(1-{4-[N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (75)    3-(Z)-(1-{4-[N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (76)    3-(Z)-[1-(4-{N-[2-(morpholin-4-yl)-ethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone-   (77)    3-(Z)-(1-{4-[N-(aminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (78)    3-(Z)-(1-{4-[N-(methylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (79)    3-(Z)-(1-{4-[N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (80)    3-(Z)-[1-(4-{N-[N-(2-dimethylamino-ethyl)-N-methyl-amino)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone-   (81)    3-(Z)-(1-{4-[N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (82)    3-(Z)-(1-{4-[N-(pyrrolidin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (83)    3-(Z)-(1-{4-[N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (84)    3-(Z)-(1-{4-[N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone-   (85)    3-(Z)-[1-(4-{N-[(morpholin-4-yl)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-dimethoxy-2-indolinone-   (86)    3-(Z)-{1-[4-(2-dimethylamino-ethoxy)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (87)    3-(Z)-{1-[4-(3-dimethylamino-propoxy)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (88)    3-(Z)-{1-[4-(2-aminocarbonyl-ethyl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone (89)    3-(Z)-{1-[4-(pyridine-2-yl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (90)    3-(Z)-{1-[4-(pyridine-3-yl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (91)    3-(Z)-{1-[4-(pyridine-4-yl)-anilino]-1-phenyl-methylidene}-5,6-dimethoxy-2-indolinone-   (92)    3-(Z)-[1-(4-nitro-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (93)    3-(Z)-1-[(4-fluoro-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (94)    3-(Z)-1-[(4-chloro-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (95)    3-(Z)-[1-(4-bromo-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (96)    3-(Z)-[1-(4-iodo-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (97)    3-(Z)-[1-(4-cyano-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (98)    3-(Z)-[1-(4-methoxy-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (99)    3-(Z)-[1-(4-ethoxy-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (100)    3-(Z)-[1-(4-trifluoromethyl-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone-   (101)    3-(Z)-[1-(4-methyl-anilino)-1-ethyl-methylidene]-5,6-di-methoxy-2-indolinone-   (102)    3-(Z)-[1-(4-methylmercapto-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone-   (103)    3-(Z)-[1-(4-aminomethyl-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone-   (104)    3-(Z)-{1-[4-(methylaminomethyl)-anilino]-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (105)    3-(Z)-{1-[4-(isopropylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (106)    3-(Z)-(1-[4-(phenylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (107)    3-(Z)-{1-[4-(ethylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (108)    3-(Z)-{1-[4-(propylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (109)    3-(Z)-{1-[4-(butylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (110)    3-(Z)-{1-[4-(isobutylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (111)    3-(Z)-{1-[4-(cyclohexylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (112)    3-(Z)-{1-[4-(benzylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (113)    3-(Z)-{1-[3-(dimethylamino-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (114)    3-(Z)-(1-{4-[(N-ethyl-N-methyl-amino)-methyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (115)    3-(Z)-{1-[4-(diethylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (116)    3-(Z)-(1-{4-[(N-methyl-N-propyl-amino)-methyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (117)    3-(Z)-(1-{4-[(N-isopropyl-N-methyl-amino)-methyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (118)    3-(Z)-(1-{4-[(N-ethyl-N-propyl-amino)-methyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (119)    3-(Z)-(1-{4-[(N-ethyl-N-isopropyl-amino)-methyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (120)    3-(Z)-{1-[4-(dipropylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (121)    3-(Z)-{1-[4-(diisopropylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (122)    3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (123)    3-(Z)-(1-{4-[(N-benzyl-N-ethyl-amino)-methyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (124)    3-(Z)-{1-[4-(dibenzylaminomethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (125)    3-(Z)-{1-[4-(pyrrolidin-1-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (126)    3-(Z)-{1-[4-(3,6-dihydro-2H-pyridine-1-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (127)    3-(Z)-{1-[4-(2,6-dimethyl-piperidin-1-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (128)    3-(Z)-{1-[4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (129)    3-(Z)-{1-[4-(azepan-1-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (130)    3-(Z)-{1-[4-(piperazin-1-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (131)    3-(Z)-{1-[4-(morpholin-4-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (132)    3-(Z)-{1-[4-(thiomorpholin-4-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (133)    3-(Z)-{1-[4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (134)    3-(Z)-{1-[4-(acetylamino-methyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (135)    3-(Z)-{1-[4-(2-amino-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (136)3-(Z)-{1-[4-(2-methylamino-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (137)    3-(Z)-{1-[4-(2-ethylamino-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (138)    3-(Z)-{1-[4-(2-dimethylamino-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (139)    3-(Z)-{1-[4-(2-diethylamino-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (140)    3-(Z)-{1-[4-(2-piperidin-1-yl-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (141)    3-(Z)-(1-{4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (142)    3-(Z)-(1-{4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (143)    3-(Z)-(1-{4-[2-(4-dimethylcarbamoyl-piperidin-1-yl)-ethyl]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (144)    3-(Z)-{1-[4-(2-acetylamino-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (145)    3-(Z)-{1-[4-(3-amino-propyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (146)    3-(Z)-{1-[4-(3-dimethylamino-propyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (147)    3-(Z)-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (148)    3-(Z)-{1-[4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (149)    3-(Z)-{1-[4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (150)    3-(Z)-{1-[4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (151)    3-(Z)-(1-{4-[N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (152)    3-(Z)-(1-{4-[N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (153)    3-(Z)-(1-{4-[N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (154)    3-(Z)-(1-{4-[N-(2-amino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (155)    3-(Z)-(1-{4-[N-(2-methylamino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (156)    3-(Z)-(1-{4-[N-(2-diethylamino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (157)    3-(Z)-(1-{4-[N-acetyl-N-(2-aminoethyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (158)    3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-ethyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (159)    3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylaminoethyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (160)    3-(Z)-(1-{4-[N-acetyl-N-(3-amino-propyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (161)    3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-propyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (162)    3-(Z)-(1-{4-[N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (163)    3-(Z)-(1-{4-[N-acetyl-N-(aminocarbonylmethyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (164)    3-(Z)-(1-{4-[N-acetyl-N-(dimethylaminocarbonylmethyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (165)    3-(Z)-(1-{4-[N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (166)    3-(Z)-(1-{4-[N-methyl-N-(aminocarbonyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (167)    3-(Z)-(1-{4-[N-methyl-N-(methylaminocarbonyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (168)    3-(Z)-(1-{4-[N-methyl-N-(dimethylaminocarbonyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (169)    3-(Z)-(1-{4-[N-methyl-N-(piperidin-1-yl-carbonyl)-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (170)    3-(Z)-(1-{4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (171)    3-(Z)-(1-{4-[N-(2-methylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (172)    3-(Z)-(1-{4-[N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (173)    3-(Z)-(1-{4-[N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (174)    3-(Z)-(1-{4-[N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (175)    3-(Z)-(1-{4-[N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (176)    3-(Z)-(1-{4-[N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (177)    3-(Z)-[1-(4-{N-[2-(morpholin-4-yl)-ethyl]-N-methylsulphonyl-amino}-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone-   (178)    3-(Z)-(1-{4-[N-(aminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (179)    3-(Z)-(1-{4-[N-(methylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (180)    3-(Z)-(1-{4-[N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (181)    3-(Z)-[1-(4-{N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone-   (182)    3-(Z)-[1-(4-{N-[N-(2-dimethylamino-ethyl)-N-methyl-amino)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone-   (183)    3-(Z)-(1-{4-[N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (184)    3-(Z)-(1-{4-[N-(pyrrolidin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (185)    3-(Z)-(1-{4-[N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (186)    3-(Z)-(1-{4-[N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone-   (187)    3-(Z)-[1-[4-{N-[(morpholin-4-yl)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino]-1-ethyl-methylidene]-5,6-dimethoxy-2-indolinone-   (188)    3-(Z)-{1-[4-(2-dimethylamino-ethoxy)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (189)    3-(Z)-{1-[4-(3-dimethylamino-propoxy)-anilino]1-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (190)    3-(Z)-{1-[4-(2-aminocarbonyl-ethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (191)    3-(Z)-{1-[4-(1H-imidazol-4-yl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (192)    3-(Z)-{1-[4-(pyridine-2-yl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (193)    3-(Z)-{1-[4-(pyridine-3-yl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (194)    3-(Z)-{1-[4-(pyridine-4-yl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone-   (195)    3-(Z)-(1-anilino-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (196)    3-(Z)-[1-(4-nitro-anilino)-1-phenyl-methylidene]-5,6-di-ethoxy-2-indolinone-   (197)    3-(Z)-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (198)    3-(Z)-[1-(4-carboxy-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (199)    3-(Z)-1-[(4-fluoro-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (200)    3-(Z)-1-[(4-chloro-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (201)    3-(Z)-[1-(4-bromo-anilino)-1-phenyl-methylidene]-5,6-di-ethoxy-2-indolinone-   (202)    3-(Z)-[1-(4-iodo-anilino)-1-phenyl-methylidene]-5,6-di-ethoxy-2-indolinone-   (203)    3-(Z)-[1-(4-cyano-anilino)-1-phenyl-methylidene]-5,6-di-ethoxy-2-indolinone-   (204)    3-(Z)-[1-(4-methoxy-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (205)    3-(Z)-[1-(4-ethoxy-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (206)    3-(Z)-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (207)    3-(Z)-[1-(4-methyl-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (208)    3-(Z)-[1-(4-methylmercapto-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (209)    3-(Z)-[1-(4-aminomethyl-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (210)    3-(Z)-{1-[4-(methylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone (211)    3-(Z)-{1-[4-(isopropylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (212)    3-(Z)-{1-[4-(phenylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (213)    3-(Z)-{1-[4-(ethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (214)    3-(Z)-{1-[4-(propylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (215)    3-(Z)-{1-[4-(butylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (216)    3-(Z)-{1-[4-(isobutylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (217)    3-(Z)-{1-[4-(cyclohexylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (218)    3-(Z)-{1-[4-(benzylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (219)    3-(Z)-{1-[4-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (220)    3-(Z)-{1-[3-(dimethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (221)    3-(Z)-(1-{4-[(N-ethyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (222)    3-(Z)-{1-[4-(diethylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (223)    3-(Z)-(1-{4-[(N-methyl-N-propyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (224)    3-(Z)-(1-{4-[(N-isopropyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (225)    3-(Z)-(1-{4-[(N-ethyl-N-propyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (226)    3-(Z)-(1-{4-[(N-ethyl-N-isopropyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (227)    3-(Z)-{1-[4-(dipropylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (228)    3-(Z)-{1-[4-(diisopropylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (229)    3-(Z)-(1-{4-[(N-benzyl-N-methyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (230)    3-(Z)-(1-{4-[(N-benzyl-N-ethyl-amino)-methyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (231)    3-(Z)-{1-[4-(dibenzylaminomethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (232)    3-(Z)-{1-[4-(pyrrolidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (233)    3-(Z)-{1-[4-(3,6-dihydro-2H-pyridine-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (234)    3-(Z)-{1-[4-(2,6-dimethyl-piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (235)    3-(Z)-{1-[4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (236)    3-(Z)-{1-[4-(azepan-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (237)    3-(Z)-{1-[4-(piperazin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (238)    3-(Z)-{1-[4-(morpholin-4-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (239)    3-(Z)-{1-[4-(thiomorpholin-4-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (240)    3-(Z)-{1-[4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (241)    3-(Z)-{1-[4-(acetylamino-methyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (242)    3-(Z)-{1-[4-(2-amino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (243)    3-(Z)-{1-[4-(2-methylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (244)    3-(Z)-{1-[4-(2-ethylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (245)    3-(Z)-{1-[4-(2-dimethylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (246)    3-(Z)-{1-[4-(2-diethylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (247)    3-(Z)-{1-[4-(2-piperidin-1-yl-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (248)    3-(Z)-(1-{4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (249)    3-(Z)-(1-{4-[2-(4-carboxy-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (250)    3-(Z)-(1-{4-[2-(4-dimethylcarbamoyl-piperidin-1-yl)-ethyl]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (251)    3-(Z)-{1-[4-(2-acetylamino-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (252)    3-(Z)-{1-[4-(3-amino-propyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (253)    3-(Z)-{1-[4-(3-dimethylamino-propyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (254)    3-(Z)-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (255)    3-(Z)-{1-[4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (256)    3-(Z)-{1[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (257)    3-(Z)-{1-[4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (258)    3-(Z)-{1-[4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (259)    3-(Z)-(1-{4-[N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (260)    3-(Z)-(1-{4-[N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (261)    3-(Z)-(1-{4-[N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (262)    3-(Z)-(1-{4-[N-(2-amino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (263)    3-(Z)-(1-{4-[N-(2-methylamino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (264)    3-(Z)-(1-{4-[N-(2-diethylamino-ethyl-carbonyl)-N-methyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (265)    3-(Z)-(1-{4-[N-acetyl-N-(2-aminoethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (266)    3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-ethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (267)    3-(Z)-(1-{4-[N-acetyl-N-(2-dimethylaminoethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (268)    3-(Z)-(1-{4-[N-acetyl-N-(3-amino-propyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (269)    3-(Z)-(1-{4-[N-acetyl-N-(3-dimethylamino-propyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (270)    3-(Z)-(1-{4-[N-acetyl-N-(2-methylamino-propyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (271)    3-(Z)-(1-{4-[N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (272)    3-(Z)-(1-{4-[N-acetyl-N-(aminocarbonylmethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (273)    3-(Z)-(1-{4-[N-acetyl-N-(dimethylaminocarbonylmethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (274)    3-(Z)-(1-{4-[N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (275)    3-(Z)-(1-{4-[N-methyl-N-(aminocarbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (276)    3-(Z)-(1-{4-[N-methyl-N-(methylaminocarbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (277)    3-(Z)-(1-{4-[N-methyl-N-(dimethylaminocarbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (278)    3-(Z)-(1-{4-[N-methyl-N-(piperidin-1-yl-carbonyl)-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (279)    3-(Z)-(1-{4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (280)    3-(Z)-(1-{4-[N-(2-methylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (281)    3-(Z)-(1-{4-[N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (282)    3-(Z)-(1-{4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (283)    3-(Z)-(1-{4-[N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (284)    3-(Z)-(1-{4-[N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (285)    3-(Z)-(1-{4-[N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (286)    3-(Z)-(1-{4-[N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (287)    3-(Z)-[1-(4-{N-[2-(morpholin-4-yl)-ethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (288)    3-(Z)-(1-{4-[N-(aminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (289)    3-(Z)-(1-{4-[N-(methylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (290)    3-(Z)-(1-{4-[N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (291)    3-(Z)-[1-(4-{N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (292)    3-(Z)-[1-(4-{N-[N-(2-dimethylamino-ethyl)-N-methyl-amino)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino)-1-phenyl-methylidene]-5,6-diethoxy-2-indolinone-   (293)    3-(Z)-(1-{4-[N-(dimethylaminocarbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (294)    3-(Z)-(1-{4-[N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (295)    3-(Z)-(1-{4-[N-(pyrrolidin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (296)    3-(Z)-(1-{4-[N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (297)    3-(Z)-(1-{4-[N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino]-anilino}-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone-   (298)    3-(Z)-[1-[4-{N-[(morpholin-4-yl)-carbonylmethyl]-N-methylsulphonyl-amino}-anilino]-1-phenyl-methylidene]-5,6-di-ethoxy-2-indolinone-   (299)    3-(Z)-{1-[4-(2-dimethylamino-ethoxy)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (300)    3-(Z)-{1-[4-(3-dimethylamino-propoxy)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (301)    3-(Z)-{1-[4-(aminocarbonylmethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (302)    3-(Z)-{1-[4-(2-aminocarbonyl-ethyl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (303)    3-(Z)-{1-[4-(1H-imidazol-4-yl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (304)    3-(Z)-{1-[4-(pyridine-2-yl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (305)    3-(Z)-{1-[4-(pyridine-3-yl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone-   (306)    3-(Z)-{1-[4-(pyridine-4-yl)-anilino]-1-phenyl-methylidene}-5,6-diethoxy-2-indolinone

EXAMPLE 12

Dry Ampoule Containing 75 mg of Active Substance per 10 ml

Composition: Active substance 75.0 mg Mannitol 50.0 mg water forinjections ad 10.0 mlPreparation:

Active substance and mannitol are dissolved in water. After packagingthe solution is freeze-dried. To produce the solution ready for use, theproduct is dissolved in water for injections.

EXAMPLE 13

Dry Ampoule Containing 35 mg of Active Substance per 2 ml

Composition: Active substance 35.0 mg Mannitol 100.0 mg water forinjections ad 2.0 mlPreparation:

Active substance and mannitol are dissolved in water. After packaging,the solution is freeze-dried.

To produce the solution ready for use, the product is dissolved in waterfor injections.

EXAMPLE 14

Tablet Containing 50 mg of Active Substance

Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maizestarch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg Preparation:

-   -   (1), (2) and (3) are mixed together and granulated with an        aqueous solution of (4). (5) is added to the dried granulated        material. From this mixture tablets are pressed, biplanar,        faceted on both sides and with a dividing notch on one side.        Diameter of the tablets: 9 mm.

EXAMPLE 15

Tablet Containing 350 mg of Active Substance

Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3)Maize starch  80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5) Magnesiumstearate  4.0 mg 600.0 mg

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side. Diameter of the tablets: 12 mm.

EXAMPLE 16

Capsules Containing 50 mg of Active Substance

Composition: (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg(3) Powdered lactose 50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mg Preparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatin capsules in acapsule filling machine.

EXAMPLE 17

Capsules Containing 350 mg of Active Substance

Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate  4.0 mg 430.0 mg Preparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatin capsules in acapsule filling machine.

EXAMPLE 18

Suppositories Containing 100 mg of Active Substance

1 Suppository Contains: Active substance 100.0 mg Polyethyleneglycol(M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mgPolyethylenesorbitan monostearate 840.0 mg 2,000.0 mg  Preparation:

The polyethyleneglycol is melted together with polyethylenesorbitanmonostearate. At 400° C. the ground active substance ishomogeneously dispersed in the melt. It is cooled to 38° C. and pouredinto slightly chilled suppository moulds.

1. A compound of the formula (I):

wherein: X denotes an oxygen or sulphur atom; R₁ denotes a C₂₋₃-alkenyl,C₂₋₃-alkynyl, aryl, aryl-C₁₋₃-alkyl, heteroaryl, heteroaryl-C₁₋₃-alkyl,trifluoromethyl or cyano group, a hydroxy, C₁₋₃-alkoxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl, aryloxy or heteroaryloxygroup, a mercapto, C₁₋₃-alkylsulphenyl, phenylsulphenyl,benzylsulphenyl, C₁₋₃-alkylsulphinyl, phenylsulphinyl, benzylsulphinyl,C₁₋₃-alkylsulphonyl, phenylsulphonyl, benzylsulphonyl, sulpho,C₁₋₃-alkoxysulphonyl, phenoxysulphonyl or benzyloxysulphonyl group, anamino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,hydroxycarbonyl-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-hydroxycarbonyl-C₁₋₃-alkylamino,C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino, phenylamino,N-phenyl-C₁₋₃-alkylamino, N,N-diphenylamino, benzylamino,N-benzyl-C₁₋₃-alkylamino, N,N-dibenzylamino, C₁₋₃-alkylcarbonylamino,benzoylamino, benzylcarbonylamino group or anN—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino group wherein the two alkylgroups are optionally replaced by a C₂₋₅-n-alkylene bridge or whereinone or both alkyl groups are optionally replaced by a phenyl or benzylgroup, a C₁₋₃-alkylsulphonylamino, phenylsulphonylamino orbenzylsulphonylamino group or an N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylaminogroup wherein the two alkyl groups are optionally replaced by aC₂₋₅-n-alkylene bridge or wherein one or both alkyl groups areoptionally replaced by a phenyl or benzyl group, an aminosulphonyl,C₁₋₃-alkylaminosulphonyl, phenylaminosulphonyl, benzylaminosulphonyl,di-(C₁₋₃-alkyl)-aminosulphonyl, N,N-diphenyl-aminosulphonyl orN,N-dibenzyl-aminosulphonyl group, a phosphono, (C₁₋₃-alkoxy)PO(H),(C₁₋₃-alkoxy)PO(C₁₋₃-alkyl), (C₁₋₃-alkoxy)PO(OH), di-(C₁₋₃-alkoxy)-PO or(C₂₋₄-n-alkylenedioxy)-PO group, a ureido group optionally mono-, di- ortrisubstituted by C₁₋₃-alkyl groups, a 4- to 7-memberedcycloalkyleneimino or cycloalkyleneiminosulphonyl group, wherein in eachcase the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group is optionally replaced by an oxygen or sulphuratom, by a sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group; R₂ denotesa hydrogen, fluorine, chlorine, bromine or iodine atom, a C₁₋₆-alkyl ortrifluoromethyl group, a hydroxy, C₁₋₃-alkoxy, mercapto,C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl, sulpho,C₁₋₃-alkoxysulphonyl, aminosulphonyl, C₁₋₃-alkylaminosulphonyl ordi-(C₁₋₃-alkyl)-aminosulphonyl group, a nitro, amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group, a C₁₋₃-alkylcarbonyl, cyano, carboxy,C₁₋₃-alkoxycarbo-nyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group, a phosphono, (C₁₋₃-alkoxy)PO(H),(C₁₋₃-alkoxy)PO(C₁₋₃-alkyl), (C₁₋₃-alkoxy)PO(OH) or di-(C₁₋₃-alkoxy)-POgroup, a 4- to 7-membered cycloalkyleneimino, cycloalkyleneiminocarbonylor cycloalkyleneiminosulphonyl group, wherein in each case the methylenegroup in the 4 position of a 6- or 7-membered cycloalkyleneimino groupis optionally replaced by an oxygen or sulphur atom, by a sulphinyl,sulphonyl, —NH or —N(C₁₋₃-alkyl) group, or R₁ and R₂ together denote amethylenedioxy, ethylenedioxy, n-propylene, n-butylene or1,4-butadienylene group; R₃ denotes a hydrogen atom, denotes aC₁₋₆-alkyl, C₃₋₇-cycloalkyl, trifluoromethyl or heteroaryl group, aphenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine,bromine or iodine atom, by a trifluoromethyl, C₁₋₃-alkyl or C₁₋₃-alkoxygroup, wherein if the phenyl or naphthyl group are disubstituted thesubstituents are identical or different and are optionally substitutedby: a hydroxy, hydroxy-C₁₋₃-alkyl or C₁₋₃-alkoxy-C₁₋₃-alkyl group, by acyano, cyano-C₁₋₃-alkyl, cyano-C₂₋₃-alkenyl, cyano-C₂₋₃-alkynyl,carboxy, carboxy-C₁₋₃-alkyl, carboxy-C₂₋₃-alkenyl, carboxy-C₂₋₃-alkynyl,C₁₋₃-alkoxycarbonyl, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl,C₁₋₃-alkoxycarbonyl-C₂₋₃-alkenyl or C₁₋₃-alkoxycarbonyl-C₂₋₃-alkynylgroup, by a C₁₋₃-alkylcarbonyl, C₁₋₃-alkylcarbonyl-C₁₋₃-al-kyl,C₁₋₃-alkylcarbonyl-C₂₋₃-alkenyl or C₁₋₃-alkylcarbo-nyl-C₂₋₃-alkynylgroup, by an aminocarbonyl, aminocarbonyl-C₁₋₃-alkyl,amino-carbonyl-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkynyl,C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,C₁₋₃-alkylaminocarbonyl-C₂₋₃-alkenyl,C₁₋₃-alkylaminocarbonyl-C₂₋₃-alkynyl, di-(C₁₋₃-alkyl)-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₂₋₃-alkenyl ordi-(C₁₋₃-alkyl)-aminocarbonyl-C₂₋₃-alkynyl group, by a nitro,nitro-C₁₋₃-alkyl, nitro-C₂₋₃-alkenyl or nitro-C₂₋₃-alkynyl group, by anamino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl or di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl group, bya C₁₋₃-alkylcarbonylamino, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,C₁₋₃-alkylsulphonylamino, C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino orN—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino-C₁₋₃-alkyl group, by a 4- to7-membered cycloalkyleneimino, cycloalkyleneiminocarbonyl,cycloalkyleneiminosulphonyl, cycloalkyleneimino-C₁₋₃-alkyl,cycloalkyleneiminocarbonyl-C₁₋₃-alkyl orcycloalkyleneiminosulphonyl-C₁₋₃-alkyl group, wherein in each case themethylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group is optionally replaced by an oxygen or sulphuratom, by a sulphinyl, sulphonyl, —NH or —N(C₁₋₃-alkyl) group, or by aheteroaryl or heteroaryl-C₁₋₃-alkyl group R₄ denotes a hydrogen atom ora C₁₋₃-alkyl group; R₅ denotes a hydrogen atom or a C₁₋₃-alkyl group andR₆ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, atrifluoromethyl or heteroaryl group, a C₁₋₃-alkoxy group optionallysubstituted by 1 to 3 fluorine atoms, an amino-C₁₋₃-alkoxy,C₁₋₃-alkylamino-C₂₋₃-alkoxy or benzylamino-C₂₋₃-alkoxy group, acycloalkyleneimino-C₂₋₃-alkoxy group with 4 to 7 ring members, adi-(C₁₋₃-alkyl)-amino-C₂₋₃-alkoxy or C₁₋₃-alkylmercapto group, a nitro,cyano, carboxy, C₁₋₃-alkoxycarbonyl, amino-carbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,piperidinocarbonyl or tetrazolyl group, a C₁₋₃-alkylcarbonylamino groupoptionally substituted at the nitrogen atom by a C₁₋₃-alkyl group, animidazolyl or piperazino group optionally substituted at the imino groupby a C₁₋₃-alkyl group, a C₁₋₄-alkyl group, which may be terminallysubstituted by a hydroxy, C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxy-carbonyl,amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, phenylamino,N-phenyl-C₁₋₃-alkylamino, phenyl-n-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino ordi-(phenyl-n-C₁₋₃-alkyl)-amino group, by a 4- to 7-memberedcycloalkyleneimino group wherein a methylene group linked to the iminogroup is optionally replaced by a carbonyl or sulphonyl group or one ortwo hydrogen atoms is optionally replaced by a C₁₋₃-alkyl group and/orin each case the methylene group in the 4 position of a 6- or 7-memberedcycloalkyleneimino group is optionally substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-n-C₁₋₃-alkylamino orN—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino group or is optionally replacedby an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or—N(C₁₋₃-alkyl) group, by a 5- to 7-membered cycloalkenyleneimino groupwherein the double bond is isolated from the nitrogen atom, by aC₄₋₇-cycloalkylamino, N—(C₁₋₃-alkyl)-C₄₋₇-cycloalkylamino orC₅₋₇-cycloalkenylamino group wherein position 1 of the ring is notinvolved in the double bond and wherein the nitrogen atom is optionallysubstituted by a C₁₋₃-alkyl group, by a C₁₋₃-alkylcarbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group, or R₆denotes a group of formula—N(R_(a))—CO—(CH₂)_(n)—R_(b)  (II), wherein R_(a) denotes a C₁₋₃-alkylgroup, n one of the numbers 0, 1 or 2 and R_(b) denotes an amino,C₁₋₄-alkylamino, phenylamino, N—(C₁₋₄-alkyl)-phenylamino, benzylamino,N—(C₁₋₄-alkyl)-benzylamino or di-(C₁₋₄-alkyl)-amino group or a 4- to7-membered cycloalkyleneimino group, wherein in each case the methylenegroup in the 4 position of a 6- or 7-membered cycloalkyleneimino groupis optionally replaced by an oxygen or sulphur atom, by a sulphinyl,sulphonyl, —NH or —N(C₁₋₃-alkyl) group, a group of formula—N(R_(c))—(CH₂)_(m)—(CO)_(o)—R_(d)  (III), wherein R_(c) denotes aC₁₋₃-alkyl, C₁₋₃-alkylcarbonyl, arylcarbonyl, benzylcarbonyl,C₁₋₃-alkylsulphonyl, arylsulphonyl or benzylsulphonyl group, m denotesone of the numbers 1, 2, 3 or 4, o denotes one of the numbers 0 or 1 andR_(d) has the meanings given for R_(b) hereinbefore or denotes adi-(C₁₋₄-alkyl)-amino-C₁₋₃-alkylamino group optionally substituted inthe 1 position by a C₁₋₃-alkyl group, or R₆ denotes anN—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group; wherein any carboxy,amino or imino group present is optionally substituted by a group whichcan be cleaved in vivo, wherein when there is an imino or amino groupthey are optionally substituted by the following groups which can becleaved in vivo: a hydroxy group, an acyl group, an allyloxycarbonylgroup, a C₁₋₁₆-alkoxycarbonyl group, a phenyl-C₁₋₆-alkoxycarbonyl group,a C₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl orR_(e)CO—O—(R_(f)CR_(g))—O—CO group wherein R_(e) denotes a C₁₋₈-alkyl,C₅₋₇-cycloalkyl, phenyl or phenyl-C₁₋₃-alkyl group, R_(f) denotes ahydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or phenyl group and R_(g)denotes a hydrogen atom, a C₁₋₃-alkyl or R_(e)CO—O—(R_(f)CR₉)—O groupwherein R_(e) to R_(g) are as hereinbefore defined, and additionally aphthalimido group may be used for an amino group, wherein when there isa carboxy group it is optionally substituted by the abovementioned estergroups which can be converted in vivo into a carboxy group, or thephysiologically acceptable salts and isomers thereof.
 2. The compoundaccording to claim 1, wherein X denotes an oxygen atom; R₁ denotes aC₁₋₃-alkoxy, trifluoromethyl, di-(C₁₋₃-alkyl)-amino, pyrrolidino orpyrrolo group, an amino or C₁₋₃-alkylamino group wherein anamino-hydrogen atom is optionally replaced by a C₁₋₃-alkylcarbonyl,phenyl-C₁₋₃-alkylcarbonyl, benzoyl, aminocarbonyl, C₁₋₃-alkylsulphonyl,phenylsulphonyl, carboxy-C₁₋₃-alkyl or C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkylgroup, or a phenyl group optionally substituted by a C₁₋₃-alkyl group;R₂ denotes a hydrogen atom or a C₁₋₃-alkoxy group or R₁ and R₂ togetherdenote a methylenedioxy group; R₃ denotes a C₁₋₃-alkyl or a phenyl groupsubstituted by a cyano, amino-C₁₋₃-alkyl orN—(C₁₋₃-alkanoyl)-amino-C₁₋₃-alkyl group; R₄ denotes a hydrogen atom; R₅denotes a hydrogen atom and R₆ denotes a hydrogen, fluorine, chlorine,bromine or iodine atom, a trifluoromethyl, 4-(C₁₋₃-alkyl)-piperazino,pyridinyl, imidazolyl, tetrazolyl, C₁₋₃-alkoxy or C₁₋₃-alkylmercaptogroup, a nitro, cyano, carboxy or C₁₋₃-alkyloxycarbonyl group or aC₁₋₃-alkylcarbonylamino group optionally substituted at the nitrogenatom by a C₁₋₃-alkyl group, a piperidinocarbonyl group or anaminocarbonyl group optionally substituted by one or two C₁₋₃-alkylgroups, a C₁₋₃-alkyl group optionally terminally substituted by anamino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, phenylamino,N-phenyl-C₁₋₃-alkylamino, phenyl-n-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino ordi-(phenyl-n-C₁₋₃-alkyl)-amino group, by a pyrrolidino, piperidino,hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholinoor piperazino group wherein the piperidino group may additionally besubstituted by one or two C₁₋₃-alkyl groups or by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl-di-(C₁₋₃-alkyl)-aminocarbonyl orN—(C₁₋₃-alkyl)-phenyl-n-C₁₋₃-alkylamino group, by a C₅₋₇-cycloalkylaminoor C₅₋₇-cycloalkenylamino group wherein position 1 of the ring is notinvolved in the double bond, by a C₁₋₃-alkylcarbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkylcarbonylamino, carboxy, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup, a C₁₋₃-alkoxy group, which is terminally substituted by an amino,C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group, a group of formula—N(R_(a))—CO—(CH₂)_(n)—R_(b)  (II), wherein R_(a) denotes a C₁₋₃-alkylgroup, n denotes one of the numbers 0, 1 or 2 and R_(b) denotes anamino, C₁₋₄-alkylamino or di-(C₁₋₄-alkyl)-amino group or a pyrrolidino,piperidino, hexamethyleneimino, morpholino, thiomorpholino,1-oxido-thiomorpholino or piperazino group, a group of formula—N(R_(c))—(CH₂)_(m)—(CO)_(o)—R_(d)  (III), wherein R_(c) denotes aC₁₋₃-alkyl, C₁₋₃-alkylcarbonyl or C₁₋₃-alkylsulphonyl group, m denotesone of the numbers 1, 2, 3 or 4, o denotes one of the numbers 0 or 1 andR_(d) has the meanings given for Rb hereinbefore or denotes adi-(C₁₋₄-alkyl)-amino-C₁₋₃-alkylamino group optionally substituted inthe 1 position by a C₁₋₃-alkyl group, or R₆ denotes anN—(C₁₋₃-alkyl)-C₁₋₃-alkylsulphonylamino group.
 3. The compound accordingto claim 2, wherein X denotes an oxygen atom; R₁ denotes a methoxy,ethoxy, trifluoromethyl, phenyl, methylphenyl, dimethylamino,pyrrolidino or pyrrolo group, an amino group which is optionallysubstituted by a methyl, carboxymethyl, methoxycarbonylmethyl, acetyl,phenylacetyl, benzoyl, methanesulphonyl, benzenesulphonyl oraminocarbonyl group; R₂ denotes a hydrogen atom, a methoxy or ethoxygroup or R₁ and R₂ together denote a methylenedioxy group; R₃ denotes anethyl group or a phenyl group substituted by a cyano, aminomethyl orN-acetyl-aminomethyl group; R₄ denotes a hydrogen atom; R₅ denotes ahydrogen atom and R₆ denotes a hydrogen, fluorine, chlorine, bromine oriodine atom, a methyl, trifluoromethyl, methoxy, ethoxy, methylmercapto,cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,dimethylaminocarbonyl, piperidinocarbonyl, nitro, 4-methyl-piperazino,imidazolyl, pyridinyl or tetrazolyl group, an ethyloxy or n-propyloxygroup terminally substituted by a dimethylamino group, a methyl or ethylgroup substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl or dimethylaminocarbonyl group, a C₁₋₃-alkyl group, whichis optionally terminally substituted by an amino, C₁₋₄-alkylamino,cyclohexylamino, benzylamino or phenylamino group wherein a hydrogenatom of the amino-nitrogen atom is optionally replaced in each case by aC₁₋₃-alkyl, benzyl, acetyl or dimethylaminocarbonyl group, by apiperidino group optionally substituted by one or two methyl groups, bya piperidino group substituted by a carboxy, methoxycarbonyl,ethoxycarbonyl or dimethylaminocarbonyl group, by a pyrrolidino,3,4-dehydro-piperidino, hexa-methyleneimino, morpholino, thiomorpholino,1-oxo-thio-morpholino or piperazino group, a C₁₋₃-alkylamino groupwherein the hydrogen atom of the amino-nitrogen atom is replaced by anethyl or n-propyl group, each of which is terminally substituted by adimethylamino group, by a C₂₋₃-alkanoyl group which is optionallysubstituted in the 2 or 3 position by an amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, pyrrolidino, piperidino, morpholino or piperazinogroup, by an aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,piperidinocarbonyl or methanesulphonyl group, wherein the C₁₋₃-alkylmoiety of the C₁₋₃-alkylamino group is further optionally substituted byan aminocarbonyl group, by a C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group wherein a C₂₋₃-alkyl moiety mayadditionally be terminally substituted by a dimethylamino group, by apyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl orpiperazinocarbonyl group, and wherein the C₂₋₃-alkyl moiety of theabove-mentioned C₁₋₃-alkylamino group is also further optionallyterminally substituted by an amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, pyrrolidino, piperidino, morpholino or piperazinogroup.
 4. The compound according to claim 3, wherein R₂ denotes ahydrogen atom.
 5. The compound according to claim 4, wherein R₁ and R₂,which are identical or different, each denote a C₁₋₃-alkoxy group. 6.The compound according to claim 1, wherein X denotes an oxygen atom; R₁denotes an amino, methoxy or ethoxy group; R₂ denotes a hydrogen atom orin position 5 a methoxy or ethoxy group; R₃ denotes a C₁₋₃-alkyl or aphenyl group substituted by a cyano, amino-C₁₋₃-alkyl orN—(C₁₋₃-alkanoyl)-amino-C₁₋₃-alkyl group; R₄ and R₅ each denote ahydrogen atom and R₆ denotes a methyl or ethyl group substituted by amethylamino, ethylamino, piperidino or4-(dimethylaminocarbonyl)-piperidino group, wherein the amino-hydrogenatom of the methylamino- and ethylamino group is replaced by a methyl orbenzyl group, an N-dimethylaminomethylcarbonyl-N-methyl-amino group oran N-acetyl-N—(C₂₋₃-alkyl)-amino group wherein the C₂₋₃-alkyl moiety ineach case is terminally substituted by a dimethylamino group.
 7. Acompound, wherein the compound is3-(Z)-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinoneor the physiologically acceptable salts and isomers thereof.
 8. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 1 and one or more inert carriers and/ordiluents.
 9. A method of treating haemangiomas, metastasisation,rheumatoid arthritis, psoriasis, ocular neovascularisation or diabeticretinopathy, comprising administering to a patient in need thereof atherapeutically effective amount of a compound according claim
 1. 10. Amethod of inhibiting tumour cell proliferation comprising contacting acell with an effective amount of a compound according to claim
 1. 11. Amethod of inhibiting tumour cell proliferation comprising administeringto a patient a therapeutically effective of a compound according toclaim
 1. 12. A method of treating solid tumours, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according claim
 1. 13. A method of inhibitingendothelial cell proliferation comprising contacting a cell with aneffective amount of a compound according to claim
 1. 14. A method ofinhibiting endothelial cell proliferation comprising administering to apatient a therapeutically effective amount of a compound according toclaim 1.